P R O C E E D I N G S

Time: 8:05 a.m.

MS. SCUDIERO: Good morning. We are ready to begin now. Sorry for a little delay.

I am Jan Scudiero. I am the Executive Secretary of this panel and a reviewer in the Division of General Restorative Neurological Devices.

The usual housekeeping matters: If you haven't signed in at the door, please do so, and pick up agendas and other meeting related information.

Before I turn over the meeting to Dr. Becker, I am required to read three statements into the record. There are two deputization of temporary voting member statements and a conflict of interest statement that were prepared for this meeting.

The first: Pursuant to the authority granted under the Medical Devices Advisory Committee charter dated October 27, 1990, and amended April 20, 1995, I appoint the following person to be a voting member of the Neurological Devices Panel for the duration of this meeting on June 15, 2004: Laura Fochtmann, M.D.

For the record, she is a Special Government Employee and is a consultant to this panel or another panel under the Medical Devices Advisory Committee. She has undergone the customary conflict of interest review and has reviewed the material to be considered at this meeting. Signed by Daniel G. Schultz, M.D., Acting Director, Center for Devices and Radiological Health, on June 9th of this year.

The other: Pursuant to the authority granted under the Medical Devices Committee charter for the Center for Devices and Radiological Health dated on October 27, 1990 and amended August 18, 1999, I appoint the following individuals as voting members for the Neurological Devices Panel for the meeting on June 15, 2004: Richard P. Malone, M.D., Irene E. Ortiz, M.D., Richard S. Wang, M.D. MPH, Dr.Public Health.

For the record, Doctors Malone, Ortiz and Wang are members of the Psychopharmacologic Drugs Advisory Committee of the Center for Drug Evaluation and Research. They are Special Government Employees who have undergone the customary conflict of interest review and have reviewed the material to be considered for this meeting. This is signed by Peter J. Pitts, until recently the Associate Commissioner for External Relations, on June 4th of this year.

The conflict of interest statement: The following announcement addresses conflict of interest issues associated with this meeting and is made part of the record to preclude even the appearance of an impropriety.

To determine if any conflict existed, the agency reviewed the submitted agenda for this meeting and all financial interests reported by the Committee participants.

The conflict of interest statutes prohibit Special Government Employees from participating in matters that could affect their or their employers' financial interest. However, the agency has determined that the participation of certain members and consultants, the need for whose services outweighs the potential conflict of interest involved, is in the best interest of the government.

Therefore, waivers were granted to Doctors Kyra Jo Becker and Laura Fochtmann for their interest in firms and issues that could potentially be affected by the panel's recommendation.

Dr. Becker's waiver involves an imputed interest, a contract to her institution for the sponsor's study in which she has no involvement and is uncompensated. Dr. Becker's waiver allows her to participate fully in today's deliberations.

Dr. Fochtmann waiver involves a contract to her institution for the sponsor's study in which she has no involvement and is uncompensated. Dr. Fochtmann waiver allows her to participate fully in today's deliberations.

Copies of these waivers may be obtained from the agency's Freedom of Information Office, Room 12A-15 of the Parklawn Building.

We would like to note for the record that the agency took into consideration certain matters regarding Dr. Mary Jensen. She reported an interest in a firm at issue but not in matters related to today's agenda. The agency has determined, therefore, that she may fully participate in all discussions.

In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participant should excuse himself or herself form such involvement, and the exclusion will be noted for the record.

With respect to all other participants, we ask, in the interest of fairness, that all persons making statements or presentations disclose any current or previous financial involvement with any firm whose products they may wish to comment upon.

I wish to announce that the August 5th and 6th tentatively scheduled meeting for this Panel was canceled, because there is no agenda for a meeting. The remaining tentatively scheduled Panel meeting for this calendar year is October 28th and 29th.

Please remember that this is a tentative date, and monitor the CDRH Panel website for updated Panel meeting information.

I would now like to turn the meeting over to our Chairperson, Dr. Kyra Becker.

CHAIRPERSON BECKER: Good morning. My name is Kyra Becker, and I am the Chairperson of this Neurological Devices Panel. I am a neurologist, and I practice at the University of Washington in Seattle.

At this meeting the panel will discuss, make recommendations and vote on a recommendation to the Food and Drug Administration on the approvability of premarket approval application supplement P970003/S50 for the Cyberonics Vagus Nerve Stimulation Therapy System.

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

We will have an open public hearing and the sponsor and FDA presentations before lunch. After lunch, the Panel will deliberate on the approvability of the PMA. Before the Panel votes, there will be another open public hearing and a time for the FDA and sponsor summations.

Before we begin this meeting, I would like to ask for the Panel members, who are generously giving their time to help the FDA in the matter at hand, and the other FDA staff seated around this table to introduce themselves. I think we are going to start at this end of the table, and I would like you to state your name, your area of expertise, your position and your affiliation.

DR. ELLENBERG: My name is Jonas Ellenberg. I am a biostatistician. I am on staff at Westat, a social services private research firm. I am a Vice President and Senior Biostatistician.

DR. JAYAM-TROUTH: I am Annapurni Jayam-Trouth. I am the Chair of Neurology at Howard University, Washington, D.C.

DR. FOCHTMANN: I am Laura Fochtmann. I am a Professor in the Department of Psychiatry at the State University of New York at Stony Brook.

DR. WANG: I am Philip Wang, a psychiatrist and epidemiologist at Harvard Medical School.

DR. JENSEN: I am Mary Lee Jensen. I am Director of Interventional Neuroradiology and a Professor of Radiology and Neurosurgery at the University of Virginia.

DR. ORTIZ: I am Irene Ortiz. I am a geriatric psychiatrist at the University of New Mexico and with the Albuquerque BA.

DR. MALONE: I am Richard Malone. I am a psychiatrist and professor of psychiatry at Drexel University, College of Medicine.

MS. WELLS: I'm Chris Wells, and I am the Consumer Representative on this Panel.

MR. BALO: I am Andy Balo, the industry rep, but I am Vice President of Regulatory Clinical at DexCom, Inc., in San Diego.

DR. WITTEN: Celia Witten. I am Division Director of the reviewing division for this product at FDA.

CHAIRPERSON BECKER: Thank you. I would like to note for the record that the voting members here at the Panel constitute a quorum as required by 21 CFR Part 14.

Next Mr. Theodore Stevens, Chief of the Restorative Devices Branch, will update the Panel on several matters deliberated on at the last meeting of the Panel on February 23, 2004. Mr. Stevens.

MR. STEVENS: Okay. I don't seem to have slides going here on the screen.

Hi. I am Ted Stevens. I am the Chief of the Restorative Devices Branch, and I will be giving a very brief update on the devices that were reviewed by this Panel previously.

At the February meeting there was advice given to the reviewing branch on the concentric medical Mercy device that remains under review in the General Surgical Devices Branch at FDA.

We have also recently published a draft guidance and a Federal Register notice for availability of vascular and neurovascular embolization devices. The comment period for that draft guidance ended on May 25th.

Finally, several devices have been cleared that are reviewed under the Orthopedic Devices Panel, but because they are devices that are also used by neurosurgeons and interventional radiologists, I thought it would be appropriate to mention them here.

We have recently cleared several PMMA cements for use in pathological fractures of the vertebral body. These 510k's were cleared based on the reclassification of PMMA bone cements. That included pathological fractures in general for the specific indication of vertebral body fractures. These 510k's included clinical data from the literature.

That concludes the update.

CHAIRPERSON BECKER: Thank you, Mr. Stevens. At this time we will proceed to the open public hearing portion of the meeting. We ask at this time that all persons addressing the Panel speak clearly into the microphone, as the transcriptionist is dependent on this means of providing an accurate record of the meeting.

Ms. Scudiero will now read a statement prepared for the open public hearings.

MS. SCUDIERO: Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making. To ensure such transparency at open public hearing sessions of the Advisory Committee meeting, FDA believes that it is important to understand the context of any individual's participation.

For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your statement to advise the committee of any financial relationship that you may have with the sponsor, its product and, if known, its direct competitors.

For example, this financial information may include the sponsor's payment of your travel, lodging or other expenses in connection with your attendance at the meeting.

Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any such financial relationship. If you choose not to address the issue of financial relationships at the beginning of the statement, it will not preclude you from speaking.

CHAIRPERSON BECKER: Prior to the meeting, there were seven requests to speak in the open public hearing, and each person has ten minutes to address the panel. They will speak in the order that the FDA received their requests to present to the panel.

Ms. Colleen Kelly, who is a patient in the study, will be the first speaker, if you want to come forward.

MS. KELLY: Hi. Is it possible for me to sit?

CHAIRPERSON BECKER: Certainly, yes.

MS. KELLY: You can hear me okay? Thank you. I am Patient 012 from Site 050 of the D-O1 study for Vagus Nerve Stimulation for the treatment of major depressive disorder. I am here unsolicited to ask you to approve the VNS in its application to depression.

I was not approached by my study site nor by Cyberonics to speak to this panel. I am here upon my own accord, inspired by my own experience, and driven by the necessity that viable alternatives must be offered to persons suffering from treatment resistant depression.

I have secured and paid for my own travel here. In fact, it would behoove me financially if this panel stalled he approval process. I have had the device for four and a half years and, based on my parameter settings, replacement surgery is imminent.

As long as I am in the study and as long as the study lingers, Cyberonics will be responsible for the cost of replacing my generator battery. So, actually, I am shooting myself in my financial foot by encouraging you to approve this device. Upon approval, I would become completely responsible medically and financially.

That said, my case and testimony may be of particular interest to this panel. I went into the study on no medications, remained off medications throughout the study, and am still on no medications.

There is no other explanation for my response other than the device itself. It is good science. Turn the device up; I respond. Turn the device down; I decline.

Let me assure you that my stoicism with medications is not noncompliance. Neither is it an indicator that I am only mildly affected with the illness and, therefore, can exist without medications. In short, I had exhausted them as well as every other treatment currently available to people with illness at this level, as did so many of my peers in this study.

I realize that most on this Panel and most in attendance here are experts in their field, be it neurology, psychology, psychiatry, or mental health administration; but there is one thing I can offer you about which you may know nothing. That is first hand knowledge of what it is like to have severe recalcitrant depression.

To do so, I ask you to imagine the unimaginable, to think the unthinkable, to experience second degree emotional burns with third degree prognosis. All you experience is pain, but with no cure. In fact, there is no viable treatment.

You can attempt to salve it. Only death solves it. But the medical community does not accept death as a cure. It asks us to continue to hang on and to continue to live, yet offers us no viable treatments. Trust me, it is not that we don't want to live. It is that we don't want to live like this.

Our illness is embedded in our physical bodies, ourselves. We are prisoners there, and our sentence is life. Menacing insomnia, isolation, fear, anxiety, sadness, hopelessness, general malaise, malingering fatigue, physical exhaustion, apathy, lack of motivation, concentration and focus, absence of pleasure, amplification of pain, agitation, sensitivity to criticism, thoughts that life isn't worth living -- You are all familiar with this short sheeted laundry list of symptoms.

Now imagine having them all at once. Imagine passing from one room to another in the house of pain where some symptoms are more prevalent than others, sometimes exacerbated by the very medications that were meant to alleviate them.

I will not bore you with the details of the pharmacopoeia that I have tried and then have failed, not to mention the acupuncture, homeopathy, herbal remedies, extreme dietary changes and supplements, light therapy, counseling, yoga and, of course, religion. What god would let a child suffer like this?

Then comes the inevitable, electroconvulsive therapy, ECT, a therapy so beyond the vernacular that it doesn't even pass an automated spellcheck. I would stop at the word, too, but as a person with treatment resistant depression, I could not stop.

I relented to this FDA approved treatment as a last resort. Average session: Three to five treatments. I had 33 nearly consecutive treatments. I lost retrograde 20 years of my life through memory loss, a dismal blessing. At least I could not remember the horrific pain that preceded it for years.

I asked you to imagine the unimaginable, to think the unthinkable. I also mentioned that you are experts in your field. What if, after battling an abusive lifelong illness, after enduring medication where side effects trumped minimal benefit, after relenting to a final last resort -- what if all that is wiped out? You are etherized on a tabula rasa, alive, yes, but no more FDA hearings, no more status, no more career. No more. Someone helps you remember where the soap is kept and helps you into the shower.

I am not here to blast the approval of ECT. Obviously enough, for better or worse, I am still here. I am here, however, to say that I am here today because of the VNS, and I ask you what do you offer someone after the last resort? What do you offer someone for whom ECT has failed?

I had an experimental study. What will the next guy get?

I would be remiss if I did not mention the epileptic community who has blazoned the way for efficacy and safety of the VNS device. For that, I am grateful.

They have shown us the risks and side effects involved since the FDA approved the device for them in 1997, and my personal heartfelt thanks go to those who engaged in experimental implantation even prior to that date. I offer my gratitude, and I share their cautious hope.

I would also like to thank them for their honesty and candor, which I found on the Cyberonics bulletin board. Without their shared experience, I know for a fact I would not have attained the success I have had with this device.

I followed their histories. I tracked and evaluated their settings and results, and I searched and researched my side effects and remedies through their personal experiences. Their trial and error resulted in my trial and success.

Because of what I learned on the chat board, I was eager to boost my amplitude to higher than 1.0 in the first three weeks of the initial depression study, and keep my settings above what later became known as efficacy threshold. As a result, I was one of the first to respond at my study site, and I continue to reap benefit from the device.

I encourage Cyberonics to reopen their bulletin board. I understand the risks involved and the abuses that were made to it, but I challenge the company to research and execute a safe environment where patients can exchange information regarding this very new modality of treatment, especially in its application to depression.

It was critical in my success. I know it would increase the success of others exploring the device as a possible treatment.

I am not going to idealize nor sentimentalize the device. I know I am one of a third who have responded to it. I know there are others who continue to suffer the burden of treatment resistant depression. I see it in their faces as I sit in the lobby and wait my turn at the site.

I know that pain. I suffered it prior to the VNS. Still, I have windows of it now and again. I am passionate, yet realistic, about the device. I do not romanticize its results for me nor dismiss its lack of results for others. I am well aware of its side effects, shortcomings, and its current experimental status. But I do know one thing. We need viable treatment options for those with recalcitrant depression, and VNS has worked for me.

In closing, I encourage this Panel to let the mental health community, both administrators and recipients, review the data and search the testimonies to decide if this is an appropriate treatment for their patients, their loved ones, themselves.

This is an option only you can provide by approving the device for its application to depression. Give us a choice, a possible key, a parole to our life sentences of depression. Thank you.

CHAIRPERSON BECKER: Thank you, Ms. Kelly.

Our next speaker will be Ms. Lydia Lewis, who is President of the Depression and Bipolar Support Alliance.

MS. LEWIS: Good morning. I want to thank the Advisory Panel for this opportunity to talk about the critical issue of treatment resistant depression. I am Lydia Lewis, and I am here as President of the Depression and Bipolar Support Alliance, a national patient-run advocacy organization representing the more than 25 million people living with depression and bipolar disorder.

I did not receive any financial support nor do I have any financial arrangement with any company for my work on behalf of patients with mood disorders. The Depression and Bipolar Support Alliance does, however, receive financial support in the form of program grants, honoraria, consulting fees or in-kind donations from Cyberonics, Inc. and a number of pharmaceutical companies. My travel to Maryland today was not paid for by Cyberonics, and I am not here to advocate for any particular therapy, including VNS, but rather for the critical need for new therapies.

While I have suffered from treatment resistant depression for my entire life and I have taken more than 20 different medications over the past 36 years, I am not here to tell my story. I am here to represent the millions of people with mood disorders who can't get well, people who desperately need better medications and treatment modalities other than pharmaceuticals.

Just about 4 million people directly contact DBSA every year. Connecting with millions touched in some way by Depression and Bipolar Support Alliance -- by depression and bipolar support make us particularly qualified to speak on their behalf.

As we all know, more than 30,000 people in the United States take their lives every year, not because they are weak or because they have a character flaw. They take their lives because they do not respond to any of the treatments currently available for depression or bipolar disorder.

At DBSA we know that new drugs and nonpharmacologic treatments are desperately needed. Far too many people are dying or living lives of quiet desperation, because they can't get sufficient relief form their symptoms of depression. The more treatments the FDA makes available, the more lives that will be saved.

Today I want to put a human face on the tragedy of treatment resistant depression. We can talk science all we want, but science will never drive home the devastating consequences our illnesses can have, if they are not treated.

The human face I want to share today is Barbie's, and I have given you all a picture of Barbie. It is on the last page of my testimony, and it is important, if you would, to look at this while I speak.

Barbie has three kids, two girls and a boy. She works as an oncology nurse. She is very patient, very smart, very kind, very funny, and very gentle. She is the nurse of choice, requested by more doctors when they admit a patient onto her unit.

People report that her care made the difference in their fight with cancer. Barbie was finally diagnosed with bipolar disorder after having been treated for depression for more than 15 years. She has been hospitalized five times for her depression.

The first two times her insurance covered some of the costs. The last three times it covered nothing. She has run through all of her retirement savings. Her last hospitalization was at a state facility and, although many of them are quite good, this one was so horrible and so scarring that she refuses to ever be hospitalized again.

She runs through the insurance money for her medication within the first two months of every year. Her parents use much of their retirement savings to help pay for her meds, and her siblings contribute as much as they can.

She has been prescribed a variety of medications. Sometimes she shakes. Sometimes she drools. A time or two she has found herself somewhere with no idea how she got there, because her mind was so fuzzy from her medication.

She balloons up in weight even though she eats next to nothing. She has no appetite at all. It is hard to find a nurse's uniform that fits. She gets very little sleep, 15 minutes, an hour at a time, no more. But she also can't concentrate enough to watch TV, read a book or anything else. So she lies there worrying, thinking about the patients she is trying to care for, even though she herself is very, very ill.

Once a week she summons up all her courage and drives, shaking and drooling, to a therapist more than an hour away. There is none closer. Every month it takes even more courage to drive two hours away to see her psychiatrist for 15 to 20 minutes. There is none closer.

They do the best they can to treat her at reduced fees, but she can still barely pay for their time, and nothing helps. Quite simply, her life is hell. She can't sleep. She can't eat. Her phone rings with creditors. She feels bad and ashamed about what her family has been forced to go through with her.

Her medication barely touches her symptoms, and because of her illness, everything she does takes tremendous courage. Let me tell you, it is exhausting to never get better. When no treatment works or you can't afford something that does, you can reach a place where there doesn't seem to be any exit.

If you haven't been there yourself, count yourself lucky. I have been there, and it is dark and full of pain and hopelessness. It is joyless and a place where nothing matters.

You can be young or old, beautiful or plain, rich or poor, erudite or illiterate. Everyone who ends up in this place feels the shame. It's hell on earth.

Barbie found herself in this place, because no matter how hard the doctors tried, nothing helped; and regardless of her kids, her husband, her wonderful parents and siblings, and the job she found so important, the despair of that place was too overwhelming.

Barbie isn't just any patient to me. She is my co-worker's sister, and I am sorry that we never met, because I know I really would have liked her. Barbie took her life three months after this picture was taken. She was 49 years old.

It is a profound honor to speak for Barbie who can no longer do so, and I hope her death will have some purpose. No one should have to live with pain like Barbie's. No one's family should have to suffer like hers, impotent to help through the long journey of one failed treatment after another.s

The suffering doesn't end when someone's life ends. Barbie's loved ones still suffer, because even in this day and age, there was nothing that could keep her from that dark place.

Tragically, aspects of Barbie's story still ring true for so many. No one's life should be wasted or ended because efficacious treatment isn't available. This is why we are all here. This is why we all must remain here.

It is too late for Barbie, but it is not too late for us to learn from her life and from her death. Her struggles and loss should inspire all of us to work tirelessly to bring better treatments to the millions of Barbies still suffering.

That is why I am here today, and why I am asking the FDA to remember those of us who desperately need better treatments. It is a race against time, and I ask you on behalf of the millions of people suffering with treatment resistant depression to please do everything you can to help us. Thank you.

CHAIRPERSON BECKER: Thank you, Ms. Lewis. The next speaker will be Ms. Laurie Sandoval, who is also a patient in the Cyberonics study.

(A SHORT VIDEO WAS SHOWN.)

MS. SANDOVAL: First of all, I have had no financial involvement with Cyberonics except travel and hotel accommodations.

Someone once said depression is like being a prisoner of the mind. It could not have been said better except in that prison I was in solitary confinement.

The video you just saw was me five years ago. No longer able to keep my depression at bay, I had just resigned the job of my dreams and lost any hope of living. At that time I was under the care of Dr. Lauren Marengel of Baylor Medical College for treatment resistant depression in which medications, therapy and, in some cases, electric convulsive therapy had not worked.

Dr. Marengel explained an experimental study for depression that Baylor was undertaking with Cyberonics using a vagus nerve stimulator device, and would I be interested in participating. Sign me up yesterday, Doc.

Living in Nevada and without -- and having the VNS device five years now, life had been wonderfully normal, without suicidal depression. That is until three months ago.

I started feeling down, rarely leaving the house, turning off the phone, and only getting out of bed to let the dogs out. Normally, when the VNS device goes off, it causes a tickling sensation in the throat, but latterly there was no sensation at all, and I prayed the battery was dead.

Calling Dr. Marengel's office, they couldn't say for sure if the device wasn't working until the battery was tested. My appointment wasn't scheduled for another month, and I wondered if i could hold on that long. I was once again a prisoner of the mind.

In Houston, I told the doctors I felt desperate, and my only hope was that the depression was being caused because the VNS battery died. Scared, I checked myself into Methodist Hospital psychiatric ward.

The good news is two days later, thanks to the incredible teams at Baylor and Cyberonics, I had surgery for a new and improved VNS device. This battery is expected to last eight to ten years.

Every day I wake up with a bead of joy in my heart, or maybe that's the pulse of my new battery. Anyway, I have no doubt that, if it were not for Cyberonics' innovation and Baylor's tireless dedication, I would not be here today. Thank you.

CHAIRPERSON BECKER: Thank you, Ms. Sandoval. I want to apologize up front if I mispronounce the next speaker's name, Mr. Irvin Muszynski, who is the Director of the Office of Health Care Systems & Financing of the American Psychiatric Association.

MR. MUSZYNSKI: Your pronunciation is perfect. Thank you.

Good morning, and I, too, would like to thank you for the opportunity to offer a few remarks here this morning about your considerations about the Cyberonics application.

As indicated, my name is Irvin Muszynski. I am the Director of the Office of Health Care Systems & Financing at the American Psychiatric Association. In that capacity, my key job responsibilities are ongoing liaison on behalf of the psychiatric community and its patients, with third party patients in both the public and private sector. That includes employers. It includes Medicare and Medicaid, insurance companies, both health and disability.

In that capacity, I would simply indicate to you that the question of chronic mental illness conditions, particular the depressive disorders, is a recurring issue in questions I get -- or I get questioned about all the time, and what can the psychiatric community do, and so on.

In fact, part of my monitoring of the evolution of the vagus nerve stimulation approach was stimulated in large part by interactions with disability insurers who face the burden and the consequences of recurring or treatment resistant depression on an ongoing basis.

So what I wanted to do here with you today is just briefly highlight the problem and its prevalence from our point of view and, secondly, to talk a little bit about the burdens and costs associated with major depressive disorder, treatment resistant depression, however we want to characterize or define that.

That is from the patient, the payer, the purchaser point of view. I think all three -- Rather than qualify it every time, let's just suggest that it is on behalf of all three, albeit they all have different kinds of interests, and I think you have heard some compelling stories about the patient point of view and, I think, what becomes a self-evident need or an overwhelming need to address the need for new treatments to begin to better help manage chronic conditions in a way that people's functioning can be restored and/or recovery is, in fact, completely enabled.

Respecting disclosure, I have absolutely no current or previous financial relationship or interest in Cyberonics. I think probably my travel is not paid for here, and so on and so forth. I think probably the only thing that would be maybe appropriate to indicate in the context of the conflict of interest is Cyberonics advertises in APA journals and publications, as does a number of its competitors that would be on the psychopharmacology side of the house. But other than that, there is no direct interest.

So briefly, what I want to do is highlight the problem, and some of this you may well be aware of. So I don't want to be overly redundant. But as you know, depression is a diagnosable mental medical condition.

The American Psychiatric Association has developed the DSM-4TR. The criteria which surround the nature and diagnosis of depression are well established, continually refined, and furthered by the Association and the medical community at large. So there is nothing new about that.

Its prevalence, as you probably may well be aware, I will rely on National Institute of Mental Health indications of prevalence which show that seven to ten percent of the United States population at any given time suffers from a diagnosable depressive disorder.

As you know, many patients are treated successfully at first line attempts. Depression is a eminently treatable disease, but the issue on the table for us and under consideration here is the significant proportion of people who fail to reach acceptable levels of functioning and wellbeing. That is the population at issue.

I will not pretend to tender -- I've reviewed literature on this subject, and I think I can say conclusively, there is no one definition of treatment resistant depression. Maybe it is failure of one or two psychopharmacological interventions within a period of six months, and so on.

I think the folks who spoke before me give you much more operational definitions of what major depressive disorder or treatment resistant depression is. But in any case, treatment resistance, from my point of view, refers to the absence of an acceptable clinical outcome; that is, sustained remission, defined in terms of depressive symptoms, severity or daily function to one or more prior adequate treatments.

So when we subdivide the entire U.S. population of seven to ten percent that have a diagnosable depressive disorder, of that group there are various ranges of who really would be defined, if you will, as the treatment resistant population, and the estimates range anywhere from 10 to 50 percent, depending on the literature review.

Let's say the reasonable man standard would be somewhere in the middle. So 20 to 30 percent of those with a diagnosable depressive disorder simply don't respond, do not have sustained remission, and the human and economic consequences of that, I think, are kind of self-evident, and I will speak to them a little bit more here in a moment.

Let's look at the consequences then from the human, the patient, point of view. I won't elaborate on that. I think you just heard it, but also from the economic point of view. Here, I want to again reemphasize, my job, my role as an advocate in the psychiatric community both for psychiatrists as medical clinicians who treat this disorder, but also based on the interaction I do with those who underwrite health insurance and disability insurance, and also employers as purchasers who want their employees back at the job functioning, or those who are in the public sector, whether on Medicaid and/or Medicare or dual eligible population, who are interested in some restoration of ability to resume some kind of reasonable life in the community.

You know, the mortality has a tremendous range with depression. It can start with suffering and anguish, but it moves to job absenteeism, mistakes, loss of job, subsequent financial distress. I think you have heard personal testimonies to this, and it contributes to familial/marital discord and community discord in a number of ways.

The consequences of this from an economic point of view or burden point of view are kind of striking. The average annual cost of folks who are mildly resistant to treatment is easily double those for those who are not resistant to treatment, and those who would be categorized by the health services research literature who are severely resistant, if you will, to treatment -- their average annual costs sometimes are fourfold those who are not resistant to treatment at all.

This is an extraordinary clinical challenge. It is an extraordinary economic challenge, since half of the annual costs associated with treating depression are accounted for by this population.

Not only is health care utilization higher -- we can measure that by prescription costs. We can measure it by hospitalization rates. We can measure it by outpatient visits and so on -- the impact is significant from a fiscal point of view.

Then there are also all sorts of indirect effects. The type of workdays that are lost by individuals in the workplaces is on average double those who are not diagnosed with a depressive disorder. The preponderance or the prevalence of individuals on short and long term disability with major depressive disorders, the cost of which is borne directly and indirectly by employers and others, is significantly higher.

So in sum, depression not only has a negative economic burden, but there is no way to quantify the burden on the patient, their family and the community at large.

As indicated with respect to disability, you may be familiar that the World Health Organization now counts depression as the fourth leading cause of disability worldwide. The trend is severely upward, and the projections, if all things hold constant, is that within roughly or so the next ten years it will become the number two or one cause worldwide of disability.

The United States in that respect is not a statistical anomaly. The trend is essentially -- It tracks the world trends.

So it is clinical and economic opportunity loss. It hampers physicians to the extent that first, second line, third line attempts cannot work, and the personal tragedy of suicide and loss of life is untold.

I think what these findings underscore is the need for early identification and effective long term management of treatment resistant depression. And given the prevalence and the reality of nonresponse often to first line treatment, the cost and burden and the residual symptoms of nonremitting depression, we think there is a significant need for new treatments.

I am not here to opine on the science. That is not my job, but I do think, from where I live in a day to day world and the kinds of folks I deal with in the public and private sector, whether insurers or purchasers or human resource individuals, that the development of new treatments for this subset of the population diagnosed with a depressive order would be a significantly welcome development, and I have no doubts at all in thinking that the cost/benefit to all of us will be quite positive in the end. Thank you.

CHAIRPERSON BECKER: Thank you, Mr. Muszynski. Our next speaker will be Charles Donovan, who is also a patient in the Cyberonics study.

MR. DONOVAN: Good morning. First of all, Cyberonics did pay for my airfare here, in coach, I might add, and for my lodging. However, I was not solicited by Cyberonics or the study investigators to come. I volunteered, and as a matter of fact, to volunteer I had to go through a third party. The study investigators would not allow Cyberonics to contact me. I was not allowed to contact them.

What I would like to do, if it is okay, is read a letter that I sent to the FDA in support of the application and make a few comments. This is a letter that I wrote before I had any idea that I would be here, let alone reading it out loud in a room full of people. It is dated May 10th, and it is addressed to the Executive Secretary, Janet Scudiero.

"Dear Doctors: I am a patient in the D-02 study, and I am writing to urge you to do everything possible in your power to unconditionally approve the vagus nerve stimulator as a treatment for chronic depression. It not just saved my life, which I really didn't care about. It changed my life.

"In the spring of 1980 I graduated from Georgetown University -- ironically, less than 30 minutes from where the panel meeting will take place. I also had my first major depressive episode that spring.

"I had accepted a job in the management training program of what is now J.P. Morgan Chase and moved to New York City after graduation. I bounced back during that summer, but the depression was always there, lurking in the background, and depressive episodes became more frequent over time.

"To keep this letter short, let's fast forward 15 years. In November of 1995 I eventually ended up in a lock-up unit of a hospital. I have very little memory of the details surrounding that hospitalization. I can only assume that my family must have had the hell scared out of them, and they didn't know what to do.

"In 1998, I was a 39-year-old man sobbing uncontrollably, hugging my parents in the doctor's office after the psychiatrist recommended shock treatments. I had a series of 15 or so. The ECT treatments did not work nor did any of the countless antidepressants I tried.

"In late 1999, I was no longer able to work. I don't know how I was able to continue to work as long as I did. I put up a long, hard fight, and it was a big mistake. The physical toll and mental toll that it took on my body was agonizing, and I am still recovering physically.

"In 2001 I was implanted with a vagus nerve stimulator. In my final depression rating interview just prior to implant with Raymond Tate, Ph.D. of St. Louis University, I simply told him that I hoped I would die on the operating table. Given the relative simplicity of the procedure, it was an irrational thing to hope for, but dying would have been the ultimate escape.

"I have no idea when the device was activated or how or when it was ramped up. As recently as a few months go, the study investigators told me that I may never know. All I can say is that my life is full of genuine happiness and joy. I don't have to fake it anymore.

"I have lost 30 pounds in the past 18 months. I exercise regularly, swimming, Pilates, running. I am not ashamed to go to a shopping mall or other public places for fear of being noticed.

"Last Saturday night I attended a small dinner party that 18 months ago I never would have gone to. I am also working on several different projects. This is the most productive I have been in many years.

"The improvement in mood occurred very gradually over many months, but every morning I wake up, and I still ask myself the same question: Is it the depression back? And by the time I get in the shower, the answer is no.

"Because the mood improvement was gradual, there was no dramatic epiphany. So at this point, I would have to say that the most remarkable thing is the staying power of the therapy. It's like the Energizer battery. It keeps going and going.

"With the information learned from the studies and the benefit of stimulation strategy that new patients would have that I did not have, many desperate patients could be helped. Unless you have personally suffered from chronic depression, you cannot truly understand it, but it is brutal.

"Again, I encourage you to approve this relatively straightforward procedure for an extremely gruesome disease. Please give the option of vagus nerve stimulation therapy to those suffering patients who are still searching for an answer, just as I had searched. Some desperate patients stop searching forever."

Last night as I was reading this letter out loud to kind of time it, terms like chronic depression and treatment resistant depression are really slang for an incurable disease or a disease that is becoming curable. I think that it diminishes the seriousness of the level of the disease. It diminishes the need for alternative therapies.

I am guilty of it in this letter. I don't adequately relay the day to day grind of white knuckling it. It is exhausting. And again, there is a casualness about the term chronic depression, but the casualness is, in effect -- It is chaos. There is chaos in the family. There is chaos between brothers and sisters and parents and husbands and wives.

I know there was chaos in my family, but I don't know the half of it, because there were certainly countless secret meetings amongst my family members saying, what are we going to do with this guy?

It takes a lot of work before you get the label, treatment resistant depression; and when you get there, you are stuck.

In 2001 I was implanted with the vagus nerve stimulator, but in November of 2000 I had my first meeting with the study investigators, and I remember it was a small office, and the psychiatric nurse was next to me, and the lead doctor was in the office.

I said to the doctor, "What are the chances of this thing helping me? You know, what are the odds?" And he was very measured and cautious in his response, and he basically said there is an inkling that there may or may not be something to this device that could improve mood. And I said to myself, inkling? I'll take it.

But when you think about it, what was I supposed to say? What were the options? Nothing. So the litmus test was "inkling," and I think that is probably true of the 4 million patients that suffer from chronic depression.

You know, there's 20 million people with depression in the United States, and there are 4 million that have chronic depression. You're talking the bottom of the barrel, and the therapy that you are deliberating about today is a therapy for people that are at the bottom of the barrel.

I just want to quickly mention, I encourage you to improve this relatively straightforward procedure. During the first three months after implant, it was clear I had absolutely no benefit from the device, but it was a very odd time, because that was when my hoarseness was the worst.

People would ask me, aren't you mad? And the answer was no. Somebody was telling me to stop. How long have I been talking?

CHAIRPERSON BECKER: A little over 10 minutes.

MR. DONOVAN: The answer was no. I mean, I wasn't happy about the hoarseness, but the hoarseness was completely subordinated to the hopes that the device would work.

Very quickly in one minute, some desperate patients stop searching forever. March 14, 2003: I found the body of my closest friend from seventh grade, dead. Thankfully, his brother, an M.D., was with me. His body was laying between the bathroom in the hallway, and his brother found on his bureau a bottle of antidepressants, but his search stopped. He ended his search.

A year before that, another classmate -- we only had 40 -- put a bullet to his head, a psychologist. And finally, at the same time of the psychologist's death, the wife of my brother's boss, the mother of seven children -- I spoke to her husband, Tony, last week. And unlike Barbie that Lydia talked about, this family is a very prominent family in St. Louis, and they had access to absolutely every possible thing out there. Money was no object, and they went out on a nationwide search for help for this beautiful, stunning woman, and they saw the freight train coming, and there was nothing they could do about it until one of the seven children found her hanging in the family home, dead at age 38.

So I've gone over. If there's any questions that you want to ask me as a patient, please do.

CHAIRPERSON BECKER: Thank you. Our next speaker will be Marna Daventort, who is also a patient in the study.

MS. DAVENTORT: After hearing everyone else speak, it is really difficult to come up here and talk about this clinically, because I had really a lot more prepared, but they have said it all. They are telling my story. Their lives have been my life.

I want you to know that I am a person who can meet any challenge. I fly airplanes. I have a Ph.D. I ride beautiful horses, and I ride them fast. I can meet any challenge, but I couldn't beat depression, not with all the knowledge that I could gain from studying it, and not with all the energy that I could put into it.

I can go over all the treatments I have been through, and I have been through it all, every kind of therapy that you can think of and every drug that any of you could think of prescribing to me, in experimental dosages often and in weird combinations that sometimes even the doctors were afraid to try. But we had to try anything, because the alternative is death, and people like me don't want to die.

I have a wonderful life now. I have a wonderful family. I never had drug or alcohol problems. I never had weight problems. I had no excuse whatsoever to be depressed, and yet I was depressed.

I think that that is what happens. A lot of times, we look at people with depression, and we think that somehow they could just do better. And I know that you can't just do better.

One reason I am here today, and Cyberonics paid my plane fare up -- It won't compensate for the salary I have lost today, but I am here because I think it is -- The single most important thing that I can do today is tell you that I was implanted three year ago.

At first there was really no dramatic result. My family says that they saw results right away. I didn't, but over the next year, especially when it became about the 18 month mark, I began to be the person that my family used to know. My Dad said he had his daughter back.

I think that, with all else I could say, all I can say to you today is that this worked for me, and the alternative for me, to put it bluntly, was to blow my brains out.

So I think that it would be unconscionable for you not to offer this treatment option to people in my position. It has never been proposed that it would be a first line of defense. It has never been proposed to be a replacement for the drug therapy or for the resolution of psychological problems.

All we are asking for is that you make this an option to people who have no options remaining. So I am not going to say everything else I had to say, other than I do want to point out that in May, since I have a compromised voice as a result of the surgery -- it comes and goes -- we did turn the device off in May to see if I would get some relief from the hoarseness for my voice; and I became depressed again.

I began to have these feelings of impending doom, and I just thought to myself, ah, you know, we can't go there again. So I am turned back on, and nobody will turn this device off again unless someone forces me to.

You have to give this opportunity to other people. That's the bottom line, and that's why I am here today. Thank you.

CHAIRPERSON BECKER: Thank you, Ms. Daventort. The final speaker will be Karmen McGuffee, who is also a patient in the study.

MS. McGUFFEE: While they are cuing the video, I would like to state that Cyberonics has accommodated me, paid for my accommodations and paid for my flight. However, I did start a new job last week, and they were not pleased that I would be gone for a couple of days. So it has not benefitted me financially at all. The video.

(A short video was shown.)

MS. McGUFFEE: That was me a little over five years ago. For me, it is very hard to define my first episode with depression. From the time I was three years old, I was a worrier. I worried about things that a toddler doesn't need to worry about: Would my sister die during the night?

In kindergarten I drove my teachers crazy. When my parents wanted to take a short trip, I insisted that they send books along with me so that I wouldn't fall behind. When I was nine, I couldn't sleep. I had nightmares constantly. I would go for days without sleeping. My mother says I would just lie in bed and cry and twist the sheets in my hands until one, two, 3:00 a.m. in the morning.

My mother tried everything that year, from traditional medicine to holistic medicine. We made a lot of adjustments in the family. It was not easy on them. All the doctors said there was nothing wrong with me except my blood sugar.

During my teen years, my family and friends thought that they were dealing with an overweight hypoglycemic, and those were my two problems. But then by the time I was 18, I graduated school with honors from high school. I had a good job as a computer graphic artist and a quality control coordinator.

I had seen a psychotherapist, and a psychiatrist had prescribed Prozac. Six months later, I decided I was cured, and I stopped. Shortly thereafter, I came home from work quite late one night, and my mother found me in my room in the fetal position on the floor, and I had scratched myself on my legs to the point of bleeding.

After a trip to the emergency room, I was admitted to the psych unit. I stayed there for six weeks. By the time I left, I was max'ed out on the dosage of Prozac that was safe for my weight, but I also had to take a booster, Tofranil.

Over the next few years I took Parnate, an MAOI, Zoloft, Effexor, Paxil, Xanax, Halcion and probably a few that I don't remember. There's a lot I don't remember. Drugs would work for six months, if I was extremely fortunate, maybe a year, and then they would have to spin that roulette wheel and come up with a new combination.

I was hospitalized several times. It was like being in a very dark, downward tunnel. I was sliding down, and I could not get out. As I mentioned, the impact on my family and friends was very high. Friendships were always very strained. I never had more than one friend at a time, and I always chased them off. I have difficulty accomplishing the smallest tasks every day.

I required constant reassurance from everyone around me. My family said they felt as though they were walking on egg shells. There was no telling what they would say that would cause me to just crumple. Sometimes I could not be left by myself for any amount of time.

When I started dating my now husband, Jason, we addressed my depression, and he told my parents, well, I've been around Karmen when she is sick; I know what I am in for. And he admitted later that he had no idea.

Sometimes my husband's only goal in the morning was how do I get Karmen up? How do I get her out the door, because if I could pick out my own clothes, I was doing good.

At work I could still function, but my performance was extremely unpredictable. My absenteeism was high, and I had a caustic temper. It caused me to be fired twice.

Just prior to VNS implantation, I was taking five medications daily, seeing a psychiatrist weekly. I was in weekly group therapy, and ECT was next on the list. From the drugs, I had a dry mouth constantly. The MAOI -- I once had a drug interaction that sent me to the emergency room. I have had memory loss, and I experienced massive weight gain.

Every time I would relapse, it was very dangerous and very scary. Each pit was worse than the last, and I always feared they would run out of drugs to try on me. Every suicidal thought that I ever had was when the drugs quit working and I was back in that pit.

I continued in anxious moments to scratch myself to bleeding. I have many scars on my body from that. In psychotherapy -- I mainly found that very frustrating. Everyone there had a reason for their depression, and I had a wonderful family, a healthy family, a good support system.

I used to tell my family, I wish that something bad had happened to me -- I had been kidnapped and abused. At least then I would have a reason to feel so bad.

So about two weeks after that video I had the surgery. I was home that same afternoon, and I returned to work the same week. My husband and mother first noticed an improvement within three to six weeks. At first, they thought they were being overly optimistic.

My mother said she felt like she was not looking into the eyes of a dead person anymore. She has told the doctors, I don't care what scale you use to measure depression; I can tell by looking in Karmen's eyes. My husband said that the dark funeral veil over my eyes was lifted, and he could see my eyes, and they twinkled.

Today I feel great. The only regular side effect I experience is the hoarseness in my voice, which I don't even notice. Whereas, I was taking five medications a day for two and a half or three years, I was taking only Wellbutrin. I was laid off of work about ten months ago, and they added Lexapro, because I wasn't dealing with that very well. It was not on my terms. But prior to my unemployment, I was even talking to my doctor about coming off of Wellbutrin.

I do not believe that VNS therapy has cured me, but it has helped in ways that words cannot express. I constantly worry about will the depression return.

I had a baby 17 months ago, and I was told at my first pregnancy appointment that I was at very high risk for postpartum depression. I had about 11 days of it, more like the blues, and today I enjoy my daughter thoroughly. I've gotten to see her first steps, and I remember them.

Thanks to VNS, I have clarity of mind. I can read books again, whereas I hadn't in years. I don't sleep away my weekends. I was able to research gastric bypass surgery, and had that a little over three years ago. I have lost 226 pounds. I have a joyful and peaceful life, and my family does, too, now.

In closing, people ask me why would you cut yourself open and have something foreign put in your neck and in your chest? My response to them is always, I had nothing to lose.

Please approve this therapy for treatment resistant depression, because it will give both patients and their families something that they have probably lost, and that is hope.

CHAIRPERSON BECKER: Thank you, Ms. McGuffee.

At this point I would like to note for the record that three patients and family members have written the FDA requesting that the agency approve the Cyberonics VNS system, and a patient also wrote to the agency asking that it not approve the VNS system.

Is anyone else here who would like to speak to the Panel now? If so, raise your hand, and come forward to the microphone. I would just like you to state your name and affiliation when you come forward, and whether or not you have any financial interest in Cyberonics.

MS. BARRETT: My name is Mary Barrett. I've been back there trying to write this in a hurry. I am in the D-02 study. I have no financial interest in Cyberonics or its competitors, and no one paid for my trip here today.

I originally had not planned on speaking, but I felt like, because I do have the device and it is important to me that you consider it for approval, I just wanted you to hear my story.

I have been treated for major depressive disorder for over 20 years. I have tried almost every antidepressant drug on the market and combination of meds. Only one medication helped relieve my depression for about four years until I developed an intolerable side effect and was no longer able to take the drug.

Other medications were of no help, and again caused intolerable side effects. I was implanted in February of 2001. It wasn't until the device parameters were turned up to a higher level that I felt consistently better for the first time since I was forced to stop taking the medication that worked.

I volunteered for the study, because it was a last resort. I can only reiterate what previous speakers have said about the pain of depression. It permeates every cell of your brain. It affects every aspect of your life, and it affects the people around you.

This past spring I have had surgery for breast cancer, radiation treatment, and a major automobile accident, things that would cause people without depression to become depressed. I know, had it not been for the VNS, I would have never been able to get through these life traumas.

The VNS has helped me and others I know that have the device get their life back, and I only ask that this device be made available as a choice for others with this horrific illness. Thank you.

CHAIRPERSON BECKER: Thank you. is there anybody else who would like to address the Panel now?

If not, I think we will proceed to the sponsor's presentation on their vagus nerve stimulation therapy system.

This system is indicated for the adjunctive, long term treatment of chronic or recurrent depression for patients who are experiencing a major depressive episode that has not had an adequate response to two or more antidepressant treatments.

I would like to remind public observers at this meeting that, while the meeting is open for public observation, public attendees may not participate except at the specific request of the Panel.

We will begin with the sponsor's presentations. The first Cyberonics presenter is Mr. Alan Totah, Vice President of Regulatory Affairs. He will then introduce the other Cyberonics presenters. Mr. Totah.

MR. TOTAH: Good morning. On behalf of Cyberonics and people in the United States living with treatment resistant depression, we thank you for meeting with us today to review the proposed depression indication for VNS therapy.

My name is Alan Totah, and I am the Cyberonics Vice President of Regulatory Affairs and Quality. I will begin today's sponsor presentation with a brief overview of the agenda, today's available presenters, VNS therapy system and regulatory history.

Dr. John Rush, Professor and Betty Jo Hay Distinguished Chair, Department of Psychiatry, UT Southwestern Medical Center, D-01 study investigator and D-02 principal investigator, will then summarize depression, treatment resistant depression or TRD, and the unmet need for an FDA approved effective and tolerable long term treatment for TRD.

Following Dr. Rush, Dr. Richard Rudolph, Cyberonics Vice President of Clinical and Medical Affairs, who prior to joining Cyberonics played a key role over a 16-year period in the development of the Effexor family of antidepressants at Wyeth, will then present study design and analysis plan, effectiveness and safety analysis, and the risks and benefits of VNS therapy. Dr. Rush will then provide closing remarks.

In addition to Dr. Rush, six other outside experts are with us today, who will be available for Q&A, representing psychiatry, biostatistics, and mechanism of action.

They are Doctors Harold Sackheim and Philip Ninan who are psychiatric investigators representing D-01, D-02, D-04 and D-05 depression studies; Doctors Phil Lavori and Sonia Davis who are providing expertise in biostatistics; and Doctors Tom Henry and Mark George, who are providing mechanism of action expertise and neuroimaging, and specifically VNS therapy PET and fMRI imaging.

In addition to the outside experts, we have a number of Cyberonics medical directors and directors here representing other disciplines to answer your questions.

We are here today to present to you the data that supports the safety and effectiveness of the VNS therapy system as an 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, with specific definitions of chronic and recurrent depression and failed adequate treatment.

There are very few devices or drugs that are indicated specifically as adjunctive, long term treatments, and there is no FDA approved safe and effective long term treatment specifically for this level of chronic or recurrent treatment resistant depression.

The VNS therapy system, the programming parameters, and the implant technique used in depression are the same as those approved and used in epilepsy. The generator is implanted just like a simple bradycardia pulse generator, and a bipolar lead is simply tunneled under the skin from the left vagus nerve where the lead electrodes are wrapped around the nerve and then down to the generator.

I am pointing out to you the generator. This is the typical implant site. We have a picture of the lead going up, and you can see this exploded view of the electrodes which are wrapped around the left vagus nerve, and we have the other elements or components of our system illustrated for you.

Typically, the device is programmed on for 30 seconds and off for five minutes on a 24/7 schedule. The typical outpatient surgery often lasts approximately one hour and is a low risk implant procedure, and surgical complications are minimal.

A magnet can be used by the patient to temporarily control side effects such as voice alteration during public speaking or singing, if necessary.

From an historical perspective, FDA's Neurological Devices Panel unanimously recommended epilepsy approval in June of 1997, and the VNS therapy system was approved by FDA on July 16, 1997. The epilepsy safety number shown on this slide are at the time of the application.

Today, over 29,000 epilepsy patients have been treated with the VNS therapy system, and we have accumulated a total of 72,000 patient years of experience.

Depression studies were started, because clinical observations from epilepsy use and findings from epilepsy, preclinical and human neuroimaging mechanism of action studies suggested that VNS had a potential antidepressant effect. Depression studies began in 1998 following IDE approval of a D-01 pilot study protocol.

Several significant regulatory historical dates that followed are: In July 1999 when FDA granted expedited review status; European CE Mark and Canadian commercial approvals were granted for the depression indication in March and April of the year 2001, based upon the D-01 results; and in January of 2002 the D-02 acute 12-week study results were unblinded and analyzed.

The primary endpoint did not reach statistical significance. However, the results did show a positive trend in favor of VNS, and a key secondary endpoint was statistically significant.

After consideration of the acute results, the proposed indication for use and the existing D-02 and D-04 protocols, a revised D-02 long term and D-02 versus D-04 standard of care prospective analysis plan was submitted to the FDA in September of 2002. The FDA notified Cyberonics that no manufacturing site inspection would be required, due to Cyberonics good compliance history.

The PMA Supplement was submitted and accepted for filing by the FDA on October 27, 2003. Since then Cyberonics has completely responded to FDA's deficiency letter regarding this PMA application.

That brings us to today's Panel meeting that is occurring just two weeks shy of the seventh anniversary of the original epilepsy panel in June of 1997. During today's meeting Cyberonics is prepared to address FDA's Panel questions and any questions the Panel members may have.

These are the studies that comprise the six-year depression program. Dr. Rudolph will present details in his presentation. There was one important revision during the program that you will hear about today.

For clarity, let me describe the reason for the revision and what was changed. When the acute study endpoint did not reach statistical significance despite a favorable trend, and significance on secondary endpoints, we decided to provide a more definitive evaluation of long term effectiveness by adding an active control for the D-02 outcomes.

The sole change indicated on this slide by a double checkmark added a one-year comparison of D-02 patients treated with adjunctive VNS plus standard of care treatment with D-04 patients treated only with standard of care treatment.

The existing D-04 protocol, which had been previously intended as a comparison with D-02, was then formally added into the statistical plan as a long term active control. This revised plan provided the FDA with comprehensive one-year clinical data and analysis on 460 patients with treatment resistant depression.

Cyberonics and its team of outside clinical, statistical and regulatory experts deemed the revised analysis plan the most appropriate for the determination of safety and effectiveness for the proposed indication for use, after careful consideration of the urgent unmet need for a long term treatment for TRD, which you certainly heard about from our patients today.

They consist of the following: First, the nonsignificant yet encouraging results from the acute, sham control phase of D-02; second, the increasing response rates seen over time in D-01 patients; thirdly, the adjunctive, meaning VNS would be added onto currently available standard of care treatments, long term proposed indication; fourth, the majority of PMA device and neurological device approval precedents did not include randomized controlled trials consistent with 21 CFR 860.7 of the regulations; fifth, D-04 study which started in the year 2000 and was originally designed to be compared with D-02 patients provides a valid, prospective, active standard of care control consistent with the proposed indication; and finally, the infeasibility and limited value of alternative long term study designs in treatment resistant depression patients relative to D-02 versus D-04 comparative analysis.

In conclusion, allow me to once again thank you for your time today, and mention that we are all here primarily because of the significant unmet need for an FDA approved informed use, safe and effective long term treatment for treatment resistant depression.

FDA initially recognized this need in 1999 when expedited review status was granted. Four and a half years later, FDA reconfirmed the continuing unmet need in their December 2003 PMAS filing letter. Please see the noted quote on the slide.

I now invite Dr. Rush to help us better understand treatment resistant depression and the significant unmet need for an effective long term treatment for TRD. Thank you.

DR. RUSH: Thank you very much, and good morning. I am John Rush. I am a full time employee of UT Southwestern, Dallas. I have provided consultation to Cyberonics and received fees for that consultation.

I am going to very briefly review for you probably much of what the Panel is quite familiar with, and certainly what you heard this morning already from the several patients. That is the importance of treatment resistant depression, its impact from a public health significance and from a personal significance impact, and provide you some sense of the kinds of patients that we are talking about that entered into the VNS studies.

So to recap what I think is quite familiar to most of you, a very common syndrome affecting 16 percent of the individuals in the U.S. in their lifetime. This is not TRD. This is major depressive disorder. Two-thirds are female, 9.5 million treated annually and, as mentioned previously, substantially disabling, second most disabling condition in the U.S., fourth worldwide currently, the most disabling condition for women in the United States presently.

It is associated with a marked increase in mortality due to suicide. Thirty thousand suicides per year have been mentioned. Eighty percent of those are attributable to depression, and increased mortality as well due to worsening of the outcome of a number of general medical conditions; for example, cardiovascular disease, but others as well clearly investigated and studied.

It is well known that depressed patients, for obvious reasons, are high utilizers of not just mental health services but general health services.

Very briefly, these slides are, I am sure, presenting you with what you know. So I'll just go very quickly over them. We 30 years ago had the stigma of depression. We didn't even recognize it much as an illness. They were seen as troubled individuals. Obviously, that is not the case. These are individuals suffering from a syndrome defined by a variety of biological abnormalities.

Thirty years ago we thought of these depressions as situational adjustment reactions, basically brief, time limited, and of modest impact on individuals' lives. When I was at the University of Pennsylvania, I was taught to treat these individuals with medication for four to six months to facilitate psychotherapy, and the need for long term medication was not recognized and was not part of training.

We now know that 60 percent of people in the first depressive episode will go on to have either a recurrent, subsequent episodes, or chronic course.

The next level of stigma is that we have now accepted it as an illness, but I think in many people's minds it is a very benign illness. In fact, it shortens life span due to the causes I previously mentioned, suicide, increased mortality from general medical conditions. It is massively disabling. I reviewed the data with you.

The third level of stigma: So now we recognize an illness. We are beginning to recognize just how profoundly severe and disabling this illness is, and costly on a human suffering basis as well as an economic basis. But the third myth that we deal with is, well, the treatments we have are really pretty good.

The fact of the matter is the treatments we have are good, but they are not good enough, and some of that is described here. So our current medications are effective. Fifty percent of symptomatic volunteers, individuals who have uncomplicated non-treatment resistant depression -- those are the individuals that typically enter randomized efficacy trials for regulatory purposes, by the way -- do respond to the first medication, and within that group of responders the substantial majority achieve a remission, virtual absence of symptoms. But that only gives us 35 to 40 percent of the uncomplicated, nonchronic, non-treatment resistant patients achieving remission, the goal of treatment with the first drug.

What about the second or the third drug? We had some discussion about that earlier. This is being evaluated, but at the moment the estimates are that somewhere between 15 and 20 percent of patients will not achieve remission with two or even three medications.

The other element in treatment is sustaining that benefit, if achieved, and I will describe that and discuss that in just a minute.

I will show you some of the data that indicates that, even in non-treatment resistant depressed patients, a substantial proportion having achieved a benefit in acute treatment and continuation phase -- so three months plus four more months, seven months -- do in fact suffer a return of the episode.

Treatment resistant depression: The field has begun to coalesce around an accepted definition. This is obviously on a continuum. There have been various staging systems to define treatment resistant depression, but studies have been launched that accept this definition as certainly a reasonable one. I think a consensus of experts would agree.

It is the lack of an adequate clinical response after at least two well delivered treatments. Looking at symptomatic volunteers from the efficacy trials that we have abundantly, as I mentioned, 50 percent respond. About 35 to 40 remit, no symptoms after the first trial.

It is also known that, if you go to the second treatment -- these are largely open trials, but there are quite a number of them -- about 20 to 25 percent of the original sample respond to the second treatment, having not responded to the first. So that gives us roughly 75 percent of the original sample.

That leaves us with about 20 to 25 percent of individuals who will not achieve the goal of response, which is short of remission, after two treatments.

So what do we know about TRD? It has actually become a focus of research over the last several years. It is quite clear that treatment resistant depression is clearly associated with worse function, worse prognosis, higher health care costs, health care utilization, increased risk of complications, including general medical problems and substance abuse, as we have already heard on an individual basis and has been shown in studies, high risk of family burden, high risk of suicide, and as you know, 8 to 15 percent of previously hospitalized depressed patients do go on to commit suicide, and the worsened mortality we talked about in terms of general medical conditions.

Importantly, treatment resistant depression has a very low response and very high relapse rate, and I will show you a little bit of data to justify that statement in a minute.

I really don't have to spend very much time on this issue, because you have heard the clinical picture of treatment resistant depression from the patients. But these individuals are exactly as described, tearful, suicidal, hopeless, desperate, hanging on by their knuckles, their fingernails, frequent users of hospitalization, emergency room, seeing psychiatrists frequently, often failing to be fully employed or even being unemployed, and a remarkable percentage on ongoing full time disability.

I would point out that in the Texas Public Health System, one-third to 40 percent of the individuals served by the Texas public sector have depression. They outnumber the individuals that are still substantial in number who have schizophrenia. This is a very serious condition.

These individuals depend heavily, as you heard, on families and others, and it really is a different kind of depression. This is not the kind of depression that enters typical efficacy trials, and I will show you a little more data.

These people have long standing disabling illness, rarely achieve sustained remission even spontaneously, have very modest responses to medication, but they are grateful to have even that. They are much more akin to congestive heart failure, chronic renal or lung disease, the kinds of chronic disabling general medical conditions, by the way, for which patients do not take their lives. Eighty percent of suicides are due to depression. This condition is so bad that people kill themselves because of it.

What about utilization? Just very briefly, one slide. This is a study we recently completed. This is the number of different medications, changes that the individuals went through, and this is an estimate of, in this case, cost but, obviously, then frequency of utilization of inpatient/outpatient, pharmaceutical and total health care utilization costs.

The point is the greater the degree of treatment resistance, the greater the use of all of these services, in, out and pharmaceutical.

Clinical management of TRD at the moment: Basically, we do not have an FDA approved treatment. Multiple medication is very common, as you heard. Which treatments, however, are best or what combinations are best is really not known. Is there a preferred series of treatment steps? What treatment to give first, second, third, and when to go to combinations -- that is really not known.

In fact, I am the principal investigator on an NINH sponsored trial called the Sequence Treatment Alternative To Relieve Depression Trial. We have just completed enrollment with over 4,000 patients, and it is a nested, multiple randomized controlled trial effort to see what to do, what is best, if the patient does not respond to the first treatment.

So they are randomized to four different switches or three different augments in the second stage, and the third stage there is again randomizations to different switching and augmenting treatments.

So we hope to have, really for the first time, randomized controlled evidence for what to do after the first treatment doesn't work, and certainly after the second treatment doesn't work.

At the moment -- and I would point out that this trial was launched in October of 1999. It is going to cost $35 million, and I think it represents the importance of TRD now in terms of the public health agenda. This has come on the radar screen.

In 1990, if you talked about this condition, people would deny it existed. But every clinician knew about it, because those are the patients we are treating.

ECT is our best treatment right now for treatment resistant depression. It does work very nicely acutely, but it does not -- it can't be used in a sustained, long term maintenance basis for easily for most patients, because of some cognitive side effects. And when you stop the treatment, as I will show you, the outcomes with ECT are not good, the treatment being discontinued.

The management of TRD involves side effects and adherence difficulties due to multiple medications, and it is known that the greater level of resistance is associated with lower response and higher relapse rates.

The reality of treatment of TRD today is keeping the patient alive, and basically you heard that from the patients. Let me give you one example. There is a case of a young man, 29-year-old graduate student, been in graduate school since age 21. He could not take the full course load. He was taking two courses, seeing a psychiatrist two to three times a week. He had been depressed for 10 years, in an episode for 10 years.

He had been on multiple medications. He had finally settled on a combination of Resperidone and Prosac 80 milligrams. That was the best that he could do. He was having panic attacks, but he was able to stay outside the hospital. He was preoccupied regularly with suicide and suicidal ideation, basically living by himself in the dorm room, totally dependent on his family, clearly ashamed of his life and what he had not become, given his peers with whom he had graduated from college, and this was one of the first patients that we actually entered into the VNS study.

That is very typical, as we have heard from the other patients, of treatment resistant depression.

What about long term outcome with what we have now? Well, here is the results with medication. pay attention to this column. This is from John Greden's recent publication. He looked at long term recurrence rates, comparing placebo and medication.

Indeed, the medication does provide a benefit, but look at the recurrence rate, and this is non-treatment resistant depression. The recurrence rate over a year is up to, in some studies, 50 percent, obviously depends on the population.

All of these individuals had responded acutely and stayed well for four more months of continuation treatment. So in non-TRD long term outcome is not as we hope.

This is another slide of the same question, a different population. This is a population that we recently treated in the Texas Medication Algorithm Project in the public sector. They were treated for a year under algorithm based conditions. So we used an algorithmic sequence with augmented resources.

The algorithm based treatment did very well as compared to treatment as usual. So this is the best outcome, and this is a measure of depressive symptoms analogous to the Hamilton, and what you see is the sustained response rates. That is, response at nine and 12 months out, 14 percent sustained remission, five percent -- and it doesn't matter, really, if it is observed case or LOCF. These are very, very remarkably low figures, much lower than you expect from, of course, RCTs with non-TRD patients.

A couple more slides on long term outcome, and then I will turn over the podium to Dr. Rudolph. This is work from Dr. Sackheim's group. These individuals that we are showing you here had a successful acute phase response to ECT, our most effective treatment for treatment resistant depression at the moment.

He then randomized patients to placebo, nortriptyline plus placebo, or the combination of Lithium and nortriptyline, followed the patients over subsequent six months. As you can see, the relapse rates in patients who had done quite well with ECT and were given the best treatment, still 40 percent were relapsed within six months, and this is under research conditions.

Eighty-four percent of those individuals relapsed with placebo. Not all these people were treatment resistant. Of course, many were, because they received ECT. If you look at the effect of treatment resistance at baseline on the long term outcome following successful ECT, you see this here.

Again, work from Dr. Sackheim's group, patients had done well with ECT, and they were designated at the beginning, blind to this outcome, whether or not they had been medication resistant -- this is one or more medication failures in the current episode -- or had not been so exposed.

You notice, in the people that had medication resistance, two-thirds of these individuals actually relapsed over the subsequent year, after successful treatment with ECT. And this is still an ongoing treatment. This is not in placebo. So these individuals have a very difficult long term course.

Finally, just to provide you with a sense of who the patients are that you are going to hear about. Let me just talk a little bit from a clinical perspective.

What this does is this is a comparison of individuals represented in the community ECT sample developed by Dr. Sackheim from multiple New York metropolitan area hospitals. These are just individuals that are in the community, are receiving ECT.

We then compare them to the individuals, all of them that enter the D-02 and D-04 studies. This is the number of adequately delivered treatments which were scorable by the antidepressant treatment history form, Dr. Sackheim's scale.

The first thing that you see is that level of treatment resistance in the VNS patients, noted in red, is far higher. Almost half, in fact, are not even included within patients who receive ECT in the community. Put the other way, half the patients receiving ECT in the community do not have the level of resistance that we are talking about with patients in the D-02 trial.

That makes some sense. Fifty percent -- Over 50 percent of these patients in the trial had already had ECT in their lifetime, and over a third in the current episode.

The number of hospitalizations in the VNS group nearly twice that for the ECT community group. So we are dealing in these studies with a very, very, very difficult, hard to treat, at the end of the line almost, depressed patient population.

I can tell you, I have done trials for 30 years. I have never ever come close to putting this level of difficult patient, difficult disease in any trial. These patients would not even come ever close to getting into a pharmaceutical trial, because the pharmaceutical trials typically exclude people that have failed on more than one treatment in the current episode.

The other comment is about what is the meaning of these numbers. I just want to help convert. This is a research definition that is extremely conservative. That is, Dr. Sackheim's scale only rates drugs that have been demonstrated to be effective in randomized controlled trials.

Many things that we do clinically with the treatment resistant depressed patient have not been subjected to randomized controlled trials. An example is a typical anti-psychotic augmentation has been subjected to one trial that has been published, and it was widely used practice.

We think it is effective. That would not count in Dr. Sackheim's ratings. To give you a sense, if in his scale there are two to three ATHF failed trials, what is the actual number of clinical trials these patients failed on? Twelve, twelve clinical trials, and I am not talking about all the combinations used, 12 medicines.

When you get to four to five, the number of clinical trials is 16. When it is six or greater, the number of clinical trials is 20. These are extremely resistant patients who are really at the end of the line.

So let me just briefly summarize. I am sure you are convinced that TRD is highly disabling. It affects a large number of people, 20 percent of people with major depression. It is a clear unmet need.

These patients have a high suicide risk. They have very low response rates, high relapse and recurrence rates with our current treatment, high utilization of health care services. They are really analogous to any of the very severe psychiatric or chronic general medicine conditions.

We have no FDA approved treatment that is effective, safe in the long run for TRD. ECT is excellent, but difficult for the reasons I have outlined previously. Multiple medications are used in combinations and in sequences for which there is virtually no evidence. Side effects and adherence, especially with multiple medications, is a huge problem, and we clearly need a treatment for these desperate but important and substantial in number depressed patients. Thank you.

Let me turn the podium over to Dr. Richard Rudolph, Vice President, who will go through the D-01 to 6 studies.

DR. RUDOLPH: Thank you, Dr. Rush. I want to start by thanking the Panel Chair, Panel secretary, Panel members and the FDA for this opportunity to provide an overview of the clinical data supporting safety and effectiveness for VNS for the indication that you are considering today, treatment resistant depression.

This is an outline of the presentation that I am going to give this morning. I am going to provide some general background, and then spend some time going over design and analysis considerations to help you better understand the effectiveness data that I will then present. Then finally, I will move on to safety data and a short set of conclusions.

Well, why did Cyberonics become interested, in the first place, in developing the VNS therapy for depression? There were a number of initial considerations that led us to believe VNS therapy might be useful for this indication.

Those consisted of anecdotal reports of mood improvement in patients in our epilepsy trials where the improvement in mood seemed to be out of proportion to the improvement in the seizure counts that the patients were experiencing.

Also, knowledge that the use of anti-convulsants have been used in the past and currently are used as mood stabilizers and augmenting agents in the treatment of depression, and the observation that electroconvulsive therapy has both antidepressant and anti-convulsant actions.

Subsequently there were some additional considerations that provided a biological rationale for the use of VNS for this indication. These included: A more formal analysis of mood changes in the epilepsy studies, which confirmed the anecdotal reports; a variety of neuroimaging data, some of which I will show you shortly; effects on neurotransmitters which showed that VNS does have effects on norepinephrine and serotonin, the normal transmitters most closely implicated in the action of antidepressant drugs; and most recently, activity in an animal antidepressant model called the 4-SWIM test in which VNS had similar effects to desipramine, a standard antidepressant drug, and clearly distinguishable from placebo.

As I indicated, we have done a variety of neuroimaging studies, and our findings from the neuroimaging studies have shown us that VNS affects a widespread array of autonomic, reticular, and limbic structures within the brain.

The immediate effects of VNS on the central nervous system implicate brain areas known to be primary and secondary vagal projections. So just what you would assume that happens.

Longer term effects of VNS on the central nervous system implicate limbic and paralimbic brain circuits associated with depression and mood regulation. An example of that is shown on this slide. These are PET images three months after the initiation of vagus nerve stimulation.

What one finds is effects, modulation in areas such as the orbitofrontal cortex, L. insula, and the Mid-Cingulate Gyrus. These are areas that are implicated in the regulation of mood.

Our six-year development program for VNS for the TRD indication consists of the studies on this slide. The most important studies, the ones I will be spending the most time on in my presentation, are the ones above the yellow bar.

Those are the D-01 study which was an open-label feasibility study, the D-02 study which had two parts, an acute phase which was a double blind randomized control of sham stimulation and active VNS therapy, and the second phrase, a long term phase in which the sham treated patients crossed over into active treatment. So all patients continued out to one year and beyond in an open label fashion.

Then the D-04 study, which is a prospective observational, which is a prospective observational study of treatment resistant depression patients treated with standard of care therapies, which we used as a control for the long term D-02 outcomes.

Other studies that were in our submission that I won't be speaking too much about were the C-03 study which is actually still enrolling -- it is a European open label study; the D-05 study which was per se not a study but a video tape assessment used to ascertain the inter-rate of reliability of those that were performing the ratings for the D-02 study; and then the D-06 study, which is a study, a pilot study in a very different population. This is an open label feasibility study in rapid cycling bipolar disorder.

Next I would like to go through some design and analysis considerations to help facilitate your understanding of the effectiveness data that I will be presenting subsequently.

There are several lines of evidence to support the effectiveness of adjunctive VNS therapy for TRD indication. The most important evidence comes from a comparison of the 12-month outcomes in the D-02 patients, and again these are patients in the long term that are receiving adjunctive VNS therapy, in comparison with the 12-month outcomes from patients in a separate study, D-04, which were enrolled as similar patients to receive only standard of care therapy.

Other evidence comes from a comparison of the D-02 acute treatment outcomes that compared VNS with sham control, and then longer term outcomes, both from the D-02 patients and form the D-01 patients in the feasibility study, particularly with a focus on the durability of their response.

This slide gives a schematic of the D-02 study design. Patients in the study were qualified during an initial 45-day period, and those that met protocol entry criteria were then implanted and randomized.

Following that, there was a two-week period during which stimulation was not turned on for any patients. It was a period for recovery from the surgery. At that point, the group that was randomized to the active VNS therapy group had their stimulators turned on, and for two weeks underwent a period of stimulation adjustment.

Whatever parameters were obtained and optimized at that period were continued for an additional eight weeks of therapy.

Meanwhile, the sham stimulation group underwent all the same procedures, but never had the output current turned on for their stimulators. So they served as the control.

Following the end of that period, the patients in the sham treatment group had the opportunity to cross over to active therapy and underwent the same procedures, and then both groups of patients continued into a long term open label phase.

During the acute phase, medications had to be fixed. So whatever medications the patients came into the study on had to remain the same. During the long term study phase, medications could be added or increased at the discretion of the investigators.

Here we have some more details on the study design. I have already covered the top part of the slide. There were 235 patients that were implanted in the study at 21 different study sites. The main inclusion criteria to be enrolled in the study were that you could be a male or female between the ages of 18 and 80 years of age. You had to have a current diagnosis of being in a major depressive episode with a background history of having chronic or recurrent depression.

Most importantly perhaps, you had to have failed at least two adequate treatment trials in the current major depressive episode as measured by standardized scale that Dr. Rush referred to before, the antidepressant treatment history form; and patients had to have a minimum score of 20 on their baseline Hamilton reading.

Here are some similar details for the D-04 study design. D-04 was a 24-month prospective observational study in which patients received standard of care treatment but no VNS. So if you think about it for a moment, essentially what we have in the D-02 study is a group of patients receiving VNS long term plus various medications at the discretion of the physicians taking care of the patients, and in the D-04 study we have a similar group of patients, but they are receiving medications only, no vagus nerve stimulation.

The D-04 study enrolled 127 patients at 13 total study sites, 12 of which were overlapping sites with the D-02 study. The main inclusion for the D-04 study were identical to the inclusion criteria for the D-02 study.

So why do we think this nonrandomized D-04 serves as an appropriate control for the D-02, a long term study? Well, for several reasons. First of all, it was a prospectively designed study for comparison with D-02 outcomes. It just wasn't randomized with D-02.

It does represent a clinically relevant control in that it is an active treatment control that corresponds to the proposed indication for VNS, which is adjunctive long term VNS therapy.

The study was done primarily at overlapping sites, as I have already indicated, and it did use the same principal enrollment criteria. Moreover, the study was conducted over a similar time period, which is important, because it helped ensure that patients would have access to the same types of treatments in terms of their standard of care therapy.

Finally, the D-04 represents a large sample size which, of course, facilitates statistical comparisons.

Now for the benefit Panel members that may not be that familiar with research methodology in depression trials, I have included some slides to provide some additional background. The first slide tells you how we measure effectiveness outcomes in depression studies.

In depression studies, effectiveness is measured by standardized validated rating scales. These may be either multi-dimensional scales -- that is, scales that cover different aspects of the depressive syndrome, and examples of this would be the Hamilton rating scale for depression, the inventory of depressive symptomatology self-report, and the Montgomery Asberg Depressing Rating Scale -- or the rating scales may be a Licher type scale like the Clinical Global Impression Scale.

The scales may be either clinician or patient rated. For the multi-dimensional scales, the way the scales are analyzed is to total all the individual items, obtain a total score, and then analyze the total score. Higher scores on these scales indicate a patient who is more severely depressed. So as you improve, your scores go down on the scales.

Here are some examples. I'll just provide some further detail on the Hamilton rating scale for depression. On the lefthand side of the slide, you see the various domains that are assessed by the scale: Mood, feelings of guilt, suicide, sleep, work, activities, psychomotor retardation and agitation, anxiety, somatic symptoms and weight loss.

A sample item from the scale is up here, and a clinical interpretation, and this is only a rough clinical guideline. This is not standardized through research, but here is a rough clinical interpretation of how you interpret the total scores and equate it to how severely ill the patient is.

Here is a similar representation for the Inventory of Depressive Symptomatology Self-report. It assesses some of the same symptoms and some symptoms not assessed by the Hamilton scale. Here is a sample item, and here is the clinical interpretation of the total scores.

One thing to note as I start to show the effectiveness results from the VNS studies is you will find that the baseline scores for the patients entered in our trial fall -- as a mean fall into the severe range on both scales.

Broadly speaking, the types of analyses that you will be seeing fall into two categories, either continuous measures or categorical outcomes analyses. The continuous outcomes analyses measure -- Probably the most prominent we used was a repeated measures linea regression. These continuous measures generally measure a change from baseline.

The categorical outcomes measure discrete categories of outcome. Commonly, these include response. Response is generally defined in the field as a 50 percent or greater improvement on the multi-dimensional scales or on the CGI, the Licher type scale, response is defined as a one or two, which corresponds to a clinician rating of Very Much or Much Improved from baseline.

We also use categorical outcomes of complete response or sometimes called remission. This equates with a patient who is well or almost completely well, and those are defined by absolute cutoff scores on the scales.

Finally, because we were concerned with this particular population that these standard definitions might underestimate the true benefit for the patients, we also included a categorization of clinical benefit derived from the literature, which categorizes different levels of improvement from the Hamilton scale. I will be presenting data from this particular categorical outcome mostly in the form of looking at the durability of response for patients in the D-01 and D-02 studies.

Now, of course, with the multiplicity of scales, it is important to identify one single primary outcome, and this slide shows you the primary analyses that were prespecified in our various statistical plans for each of the important studies I will be talking about today.

In the D-02 acute study the primary analyses were response rates after 12 weeks of therapy determined from the Hamilton rating scale. So that is the 50 percent or greater improvement.

For the D-02 long term study the primary analysis was the repeated measures linear regression analysis of the Hamilton scores over 12 months, estimating the change over time.

For the D-02 versus D-04 comparison, the primary analysis was a repeated measures linear regression analysis of the IDS scores over 12 months, estimating the monthly difference between the D-02 and D-04 patients, in other words a linear study effect.

You may be wondering why we had this transition through different scales and different types of analysis. So let me explain that up front.

When we had the opportunity to revise the statistical plan, which was necessitated by the finding in the acute study that there were trends and some positive findings on secondary outcomes, but the primary outcome failed to reach statistical significance, we then moved to a repeated measures rather than a categorical outcome, primarily because in prior communications with the FDA they had expressed some preference for that as an outcome, and also because it is a more sensitive measure for finding differences between treatment groups.

Then when we moved on to the D-02 and D-04 comparison, having committed ourselves to the repeated measures linear regression approach, we were kind of forced into using the IDS as the primary scale, because the D-02 study only had a baseline and a 12-month measurement on the Hamilton, and the repeated measures approach requires multiple observations over time, which were present for the IDS but not for the Hamilton. Therefore, we chose the IDS for those particular set of analyses or at least for the primary analysis.

So with that as background, let me move on to a review of the primary data that supports an effectiveness claim for VNS for the TRD indication. I am going to start with the most important evidence. That comes from a comparison of the D-02 results versus the D-04 results over 12 months of treatment.

Let's start by looking at the flow of the D-02 study participants through the long term phase. You will recall that I said 235 patients were initially implanted in the D-02 acute study; 233 of those patients continued into the long term phase and constitute our long term safety population.

Our statistical plan prespecified that analyses would be done primarily using an evaluable efficacy subset of patients, and that included 205 of those 233 patients. The reason for excluding 28 patients are shown in the middle box here on the slide.

The majority of those patients are: 21 were patients in the sham control group that were excluded, because after the sham period, their Hamilton score was no longer above 18, which was a prespecified criteria.

Now I would like to point out -- I know in the FDA review material that you received, there was a mention that 20 percent of the patients had a placebo effect, and I want to distinguish that from a placebo response, that it was an effect based on patients falling below 18, but that should not be confused with a placebo response which would require the definition that a patient improve 50 percent or more. In fact, only 10 percent of the patients improved to the extent that they could be called a placebo responder.

The other seven patients were excluded from the treatment group, and they were excluded either because they didn't have long term data or because three did not meet acute phase continuation criteria that were also prespecified in the statistical plan.

For the D-04 study there were 127 patients that were enrolled. Three were excluded from the evaluable efficacy analyses for the reasons shown on this slide.

When we analyzed the patients for their baseline characteristics, we found that they were quite comparable. This is just one of several slides. All told, we analyzed about 20 different baseline characteristics. Only three of them were statistically different between the two groups, and those are shown on this slide in yellow highlighting, along with some of the additional 19 characteristics which I thought would be of most interest to the Panel members.

So let's start with the ones that were statistically different. The first one was ethnic distribution. There was a higher percentage of Caucasians in the D-02 group, but this is probably clinically irrelevant, since as you can see in both groups, they were at least 90 percent Caucasian.

The second difference was in the number of lifetime episodes of depression. The D-04 group had a higher proportion of patients in the category of more than 10 lifetime episodes.

Then the third area of difference was in the percentage of patients that had had exposure to ECT, and both in the current episode and lifetime there was a higher percentage of patients with ECT exposure in the D-02 group.

So one take-home message from this slide and the other information I have given you is that these patients are very comparable at baseline. Also a take-home point from this slide is some indication of just how extraordinarily severely ill and treatment resistant these patients are.

For instance, you can see in terms of the average duration of illness over the lifetime and in the current episode, these are very lengthy illnesses. Patients as a mean had been sick for at least 25 years in their lifetime, and at least four years in the current episode. In fact, fully two-thirds of the patients were actually in a chronic major depressive episode, defined as an episode lasting continuously two or more years.

The primary analysis for comparing the D-02 and D-04 outcomes was a repeated measures linear regression of the IDS scores. That is illustrated on this slide. Now for point of clarity, I should say that the actual graph is drawn from actual raw scores and not from the repeated measures model. I did that for the sake of presentation clarity, but the statistical comparison comes from the primary repeated measures model.

What you will note is the D-04 patients shown in the light blue dotted line improved very little during the course of 12 months of treatment with access to every accepted therapy, every legal therapy, and a lot of churning through therapies.

By contrast, the patients in the D-02 group receiving adjunctive VNS, shown in the solid burnt orange color, improved to a greater degree. That improvement increases. That is the difference between not only the absolute improvement but also the difference between the two groups improves as time marches on through the year, and the comparison is highly statistically significant with a p-value of less than 0.001.

We did a series of alternate methodologic approaches to the data to test the robustness of the data. These included doing the primary analysis on the intent to treat population rather than this efficacy evaluable population. So all patients were included in this analysis, all 235 D-02 patients, all 127 D-04 patients, and that analysis retained statistical significance at the less than 0.001 level.

We also did an analysis where we looked at just the overlapping sites, so just the common sites to both D-02 and D-04, patients from those sites. Again, statistical significance was retained, in this case at a level of 0.002.

The results from the primary analysis were confirmed by a variety of secondary analyses. Here we are looking at the secondary analysis that examines the change in Hamilton scores from baseline to 12 months. Remember, we just had a baseline in the 12 month scores available on the Hamilton.

What one observes is that in the D-02 group there is about an eight-point decrease in the Hamilton score over the course of a year. Again, decreases signify improvement, versus about a five-point improvement in the D-04 patients. That result is statistically significant.

On a variety of secondary outcomes looking at response rates and complete response or remission rates, we find the following. Results from the IDS scale are shown here, from the Hamilton scale here. First we look at response, and then we look at complete response.

So response based on the IDS scale was 22 percent for the D-02 group and 12 percent for the D-04 group. Complete response was 15 versus 4 percent. on the Hamilton scale, the response in the treated group with adjunctive VNS was 30 percent. For the D-04 group it was 13 percent. In terms of complete response it was 17 versus 7 percent. All these comparisons are statistically significant.

One more, using the Clinical Global Impressions as a measure of response where a 1 or 2 corresponding to a clinician rating of Much or Very Much Improved equates with response, we found almost a threefold difference between the groups, with 37 percent of the D-02 patients and only 12 percent of the D-04 patients reaching the response criteria, a result that was statistically significant at a robust level.

So in summary for this section of slides, what we found were comparable, highly treatment resistant groups at baseline, a statistically significant result favoring adjunctive VNS therapy on the primary analysis, statistical significance in both evaluable efficacy analyses and ITT analyses, and statistical significance retained in the subset of patients that come only from the overlapping sites enrolling both D-02 and D-04 patients, and we found that statistically and clinically significant differences were confirmed by secondary analyses using multiple outcome measures, the categorical outcomes being a more appropriate way to assess clinical outcome.

Now because our control was a nonrandomized one, we were very concerned about potential sources of bias or other explanations for the outcome other than the VNS was contributing to the better improvement in the D-02 patients. This slide in a picture way tries to give you what we were most concerned about.

We were certainly concerned about the influence of baseline differences on patients, the influence of medications and electroconvulsive therapy, and I am going to deal with those three right now and show you why those are not the explanations for why the D-02 patients are getting better, and then i am going to address the issue of placebo response a little later in my presentation.

So let's start with baseline characteristics. Baseline characteristics do not explain why the D-02 patients are doing better. Why is that? Well, first of all, there were few significant differences between the D-02 and D-04 on baseline characteristics, as I have already demonstrated. However, we did take an additional measure that was prespecified in our statistical plan.

That was to incorporate a propensity adjustment strategy to provide additional insurance that potential bias associated with the imbalance of measured baseline covariates was removed. For nonstatisticians, such as me, let me try to give you a one-slide lesson on what propensity is all about, because it may be a new concept for some of you.

It is a technique that is particularly suitable for adjusting nonrandom treatment assignment. So it is particularly suitable for this comparison with the D-04 group.

In this particular strategy, you calculate a propensity score, and that score represents a conditional probability of assignment to a group, given a set of measured covariates. So it is a way of encompassing a whole large variety of different characteristics in a single score.

The way we used it was to incorporate it in all analyses of effectiveness and, when we did so, we found that the propensity score did not contribute to the primary repeated measures analysis' statistical significance.

Now the limitation of propensity analysis is that it can only address measured covariates or measured characteristics. It cannot address those that are unmeasured. We do not think, however, that unmeasured covariates are likely to account for the differences either, and the reasons for that are that, first of all, all or nearly all of the covariates that have a well established literature behind them were things that we measured and accounted for.

Furthermore, we think that, to the extent unmeasured covariates might be present, they are very likely to be equally distributed between the D-02 and D-04 groups, because the sample sizes for both D-02 and D-04 are quite large or, if they are not equally distributed, that would probably be because they are so rare that they would be unimportant in terms of affecting outcome.

The second issue that I would like to address is the influence of medications and electroconvulsive therapy. Obviously, this was a major consideration for us, because the way the trials were set up is patients in both groups could have access to virtually every therapy that was legally marketed.

That raises the question of whether, in the end, in fact, the treatment that the patients received as adjunctive treatment for the D-02 and the standard of care treatment for D-04 are indeed comparable.

So we have done a number of analysis to address that issue. The first thing we did was simply to look at the use of new treatments during the 12-month outcome. That is, the addition of a new medication or significant increase in an existing medication, based on those ATHF criteria.

What we found was that, among D-02 responders, 56 percent of the patients added or increased a medication during the 12 months. In contrast, 77 percent of the nonresponders and 81 percent of the D-04 responders did so, differences both of which were statistically different from the D-02 responders.

So this is highly suggestive that the benefit the D-02 responders are deriving is coming from VNS, because they are actually using less medication as time goes on.

That wasn't enough for us, however. We wanted to address this even further. So we undertook a series of censored analyses which we felt would be a rather conservative way to address this potential area of bias.

The censored analysis that I will be sharing with you this morning was the most conservative of a set that we did. In this analysis the D-02 patient scores are censored at the first significant increase or addition of an antidepressant medication.

At that point, what we do is drag forward the last score prior to censoring for those patients into the subsequent observation periods used in the repeated measures in your regression analysis of its scores.

This has the effect of truncating the VNS benefit. So it is somewhat unfair to the VNS. Even in the absence of medication, it is unfair to the VNS group, because it truncates any ongoing or increasing benefit they might obtain from VNS to, in this case, an average of seven months out of the 12 months of treatment.

At the same time, the D-04 patient scores are uncensored. They get the benefit of the full 12 months of treatment with unlimited treatment changes.

This slide shows you the results from that censored analysis. First of all, in the blue line were the results we saw before on an earlier slide for the D-04 patients on the repeated measures linear regression analysis of its scores. The bottom burnt orange line are the scores or the line that we saw before for the D-02 patients uncensored.

The censored line for the D-02 patients is shown in the line in the middle in the yellow color. So not surprisingly, once censored, the D-02 scores aren't as good, and yet there still is a good amount of change.

You can see as a change per month from baseline, uncensored is here, and for the D-02 censored scores it is still a good amount of change, and as a change from baseline both are statistically significant.

More importantly, if we look at the average difference per month versus the D-04 groups, here are the uncensored values that we looked at before. The average change per month on the IDS was a difference of .397 which, as we saw, was statistically significant.

Censored, actually somewhat to our surprise because we didn't expect this in this sensitivity analysis, didn't reach statistical significance, but it came awfully close at .052.

So we conclude that differences in outcomes between the D-02 and D-04 patients are not attributable to baseline characteristics. In fact, the results were the same with and without propensity adjustment, nor are they attributable to concomitant antidepressant medication or ECT, and I should mention that in the censored analysis medication changes always preceded an attempt at ECT. So they are accounted for in the censored analysis.

So the differences in outcomes between the two groups are also not attributed to concomitant antidepressant medication or ECT. The D-02 responders had fewer medication changes, and the D-02 patients, even censored for concomitant treatment changes, still improved more than the D-04 patients, uncensored, but didn't quite reach statistical significance.

Additional evidence for the effectiveness of VNS therapy comes from a number of datasets indicated on this slide. First, let me talk about the findings from the D-02 acute study. That was the randomized control of VNS versus sham treatment. The primary outcome measure was a response on the Hamilton. That is a 50 percent improvement.

There was a numerical trend for the treated group shown in orange to be better than the sham group of 15 versus 10 percent. This numerical trend held up through all the analyses, but it rarely reached statistical significance.

It did not reach statistical significance on the primary outcome. It did occasionally reach statistical significance on secondary outcomes such as the response from the IDS where the slightly larger differential of 17 versus 8 percent in response rates was statistically significant.

In the long term, you won't be surprised if I tell you on the repeated measures of the Hamilton scores compared to baseline, that was statistically significant. Here I have chosen to display the longer term results in terms of the categorical outcomes. What you will note is that, regardless of what scale is used, whether the IDS, the Hamilton scale or Montgomery Asberg scale, there is an accruing response over time as the patients continue from three months out to one year.

AS I indicated before, for these very treatment resistant patients these traditional research definitions may understate the true benefit to the patient. That is consistent with other very chronic and intransigent disorders such as obsessive compulsive disorder or schizophrenia. We sometimes accept a lower threshold for response. So we did use the clinical benefit categories that I showed you on an earlier study.

If you do that, in addition to the 30 percent of patients that were responders based on the Hamilton scale using the traditional research definition, you can pick up maybe another 25 percent of patients that fall into this category of a 25 to 49 percent improvement in the Hamilton, which could be meaningful in terms of producing some significant benefit for the patient, even in terms of functional outcomes.

So all told, when you add all those categories together, maybe up to slightly more than half of the patients do achieve some at least meaningful benefit during 12 months of VNS therapy.

Now, of course, those types of analyses, particularly when you are going from three to 12 months, do beg the question of which are those patients in 12 months? Are they the same patients at three months, and you are just adding more patients to it or is it a total different group of patients?

Obviously, what we would most like to see is that we are adding patients, and the patients that do benefit initially continue to benefit. This is a very important point with VNS therapy, as you have already probably come to appreciate from Dr. Rush's presentation and from hearing from some of the patients.

In this TRD population it is very unlikely that patients are going to respond, but even more stunning it is extremely unlikely that, once having responded, they are going to retain it. So while not controlled, I think these are some of the most persuasive data as to VNS's long term effectiveness.

So for instance, using the categories on the previous slide we found at the end of three months in the D-02 study there were 56 patients that fell into the extraordinary, highly meaningful or what was labeled meaningful clinical benefit, those patients that had at least a 25 percent improvement on the Hamilton score.

So after an additional nine months of therapy, what happens to those patients? Well, 41 of those patients continue to be maintained in one of these categories, and only 15 patients fall out of that category. So 73 percent of the patients all told maintained at least a meaningful clinical benefit from three to 12 months with continued adjunctive VNS therapy.

We can use these same type of analyses, which we refer to as SHIF tables, and this is just a pictorial form of that, to ask what happens to the patients that don't benefit after three months. You already heard from the patients that in some cases it takes a long time to derive benefit, and that is illustrated here.

There were 118 patients that after three months did not fall into those more desirable categories of extraordinary, highly meaningful or meaningful clinical benefit, and after an additional nine months of therapy 56 of the 118, or nearly half, did transition into at least the meaningful category of clinical benefit.

So there is some value-- There appears to be some value in continuing VNS therapy even beyond three months in patients that don't initially respond.

Then finally for the effectiveness data, I want to end with results from the D-01 feasibility study, so we don't shortchange that. The primary outcome identified in that protocol was response rate on the Hamilton.

After three months of therapy you see that 31 percent of the patients were responders, Fifteen percent were in complete response, and at the 12 month point 45 percent of the D-01 patients were responders, and 27 percent were complete responders.

Again, we can do that type of SHIF table analysis, and here are the results for the D-01 study, again using the same categories of clinical benefit. There were 30 patients after three months that were in those desirable categories, and after an additional nine months of therapy 23 of those 30 patients maintained at least a meaningful clinical benefit, and that was 77 percent of the patients.

I promised before that I would address the issue of placebo response. For those of you that are very familiar with depression studies, you know this is a major issue in doing clinical trials in drugs, at least with the more common type of depression. Hopefully, you are already getting an appreciation that it is not as much of an issue with treatment resistant depression, and I will show you why.

There are a number of reasons why improvements in the D-02 patients are not readily attributable to a placebo effect. First of all, I personally think the most persuasive is that we did show statistically significant differences in the D-02-D-04 comparison where we are actually comparing two active treatment regimens.

Moreover, just some general considerations lead us down the road that placebo response is a very unlikely explanation for the D-02 patients' outcomes. First of all, published literature tells us that placebo response rate in this treatment resistant group, unlike more common depression, is very low and the numbers that are cited in the literature are generally between zero and ten percent.

I think more compelling is that placebo response by nature is not usually sustained for 12 months, even in more common depression. There is a good literature now characterizing the pattern of placebo response, and what that literature tells us is that placebo response tends to occur early and is not persistent or sustained.

Then, too, consider that as you saw in some of the data that Dr. Rush presented, even in active treatment maintenance of patients -- and he showed you data from the ECT responders. Even when those patients are not on placebo but in active treatment, their maintenance of response is very poor, and this is another view of data that Dr. Rush showed you earlier, just a simpler presentation using bars rather than survival analysis curves.

Again, to remind you of the findings, following successful ECTs -- these are all ECT responders -- and then following patients in Dr. Sackheim's study out to one year in a naturalistic setting, 68 percent of the patients who had a prior history of medication resistance, and that could be as little as resistance to one drug -- 68 percent of those patients relapsed over the year, which was twice as high as the relapse rate in patients without an adequate medication trial prior to ECT.

We used those observations to do one exploratory analysis that I would like to share with you. There is no statistical values here, because it was just an exploratory analysis, and we didn't do statistical testing. But we asked ourselves what would happen if we just looked at the chronic subset of patients from D-02 and D-04?

Remember, two-thirds of the patients were in a chronic episode, and that is defined as a continuous episode of two or more years. These are the patients you would expect are the least likely to be subject to some type of placebo response. So we wanted to see if their overall response was similar to the total group.

That is indeed what we found. Here you see the overall response on the Hamilton scale was 29 percent for this group and 10 percent for the D-04 group, and complete response was 14 versus 3 percent. So percentages very similar to the overall group.

So in summary for this section, we found consistent numerical advantages for acute VNS therapy over sham control. Although it didn't reach statistical significance on the primary outcome, it was statistically significant on a few of the secondary outcomes. So it lends at least supporting evidence for VNS's effectiveness.

We saw increasing improvement of responders and complete responders over time, and probably most importantly, we saw improvements during adjunctive VNS therapy that were sustained at a high rate.

By contrast, placebo response in depression studies or depression in general tends to occur early and is not sustained. And even in medication resistant ECT responders, relapse is very high, even during active continuation therapy.

Next I would like to provide a very quick summary of the safety data that was in our application. Our safety database consisted of a pool of patients from the D-01, D-02 and D-03 groups or studies. That encompassed 342 patients and, I think, importantly, 689 total patient years of exposure.

The common adverse events that were obtained in the depression studies are similar to what we experienced in the epilepsy studies and epilepsy clinical use. They are listed here on this slide as defined by those events that occurred at least at a five percent incidence during acute treatment in the D-02 group and at a rate at least one and a half times that in the sham control, a sort of convention that helps sort out treatment related side effects from those that aren't treatment related.

The most common side effect that we observed was voice alteration in 68 percent of the therapy group, and the other very common effects, cough increase, shortness of breath, and swallowing difficulties, as well as some discomfort at the site of stimulation, whether that is pain or peresthesias, are all commonly known to occur with VNS therapy when it is used for the treatment of epilepsy.

These different side effects are generally mild to moderate, and most often, particularly the ones on the top of the list, are effects that only occur when the stimulator is actually on. So they may only be experienced by the patient during the 30 seconds that the stimulator is typically on, and then they don't experience them for the five minutes that it is off.

Also, the events tend to decrease over time, or at least the reporting of the events decrease over time, as illustrated by this analysis. Here we are looking at a cohort of patients that report these more frequent adverse events during the first three months of therapy, and then have continuous observations over 12 months of therapy so we can track the persistence of disappearance of that event over 12 months.

So for example, if we just look at the first one here, cough increase, what we found was that there were 55 patients -- you probably can't see the numbers too well, but there were 55 patients that reported this particular adverse event in the D-02 study during the first three months of stimulation, and then over the course of the next nine months their reporting of that side effect decreases, so that by the period nine to 12 months only 11 of the original 55 patients are still reporting that adverse event.

You see a similar pattern throughout all these common side effects, although some decrease to a lesser extent than others, like there still is a fair degree of persistence on the voice alteration. Not too surprising, since it is a direct effect of stimulating the vagus nerve.

Overall, I think very importantly, these adverse events are very well tolerated, and that is as evidence by this slide. Here we are looking at adverse event related discontinuation rates from the D-01 and D-02 studies at the time of our data cutoff for the submission.

That encompassed at least two years of experience for all the D-01 patients and at least one year for the D-02 patients. You will observe that only three percent in each of those two studies had discontinued during that time period specifically related to an adverse event.

This, I think, compares very favorably with what you see in typical drug trials where maybe 10 or even more than 10 percent of patients will discontinue for adverse events even over a short term trial lasting eight to 12 weeks.

In our review of safety, we were particularly focused on some issues that might be specific to depressed patients or the disorder of depression, and the one that we were most focused on was suicide.

Now probably all the Panel members are very sensitive to this, because there has been a lot in the public press recently about concerns that antidepressant drugs may very rarely provoke suicidal type thinking in patients, particularly pediatric patients, which has been the recent focus.

So we looked at this very carefully. First, here is the results for the pool of the D-01, 02 and 03 studies, 342 patients. We have the incidence of suicide attempts per patient year here. That works out to 3.5 percent, and actual suicide 0.4 percent.

The first thing we did was compare that to published literature. There is a nice review by Khan and Co-Workers. It is a very large review, as you can see. It encompasses almost 20,000 patients. Those patients are derived from the FDA summary bases of approval for seven different antidepressant drugs.

What Khan and Co-Workers found in a less treatment resistant group was suicide attempt rates of 2.9 percent, and actual suicide of 0.8 percent per patient year in the combined active treatment groups, and here are data also for the placebo group.

So we think the rates for the VNS group compare quite favorably with this. We also had the ability to look specifically at suicide ideation in the form of the third item of the Hamilton scale, which measures suicidal ideation.

What we were able to do here is use a standard definition that the pharmaceutical manufacturers or sponsors use, which is to look for the percentage of patients that have a two-point increase from baseline in their third score on the Hamilton.

We compared the experience in the VNS group to two control groups. First, in the acute D-02 trial, we compared the VNS group with the sham control group, and you can see similar rates. Two percent of the actively treated VNS patient and three percent of the sham treated patients had these two-point increases.

Then for more long term exposure we were able to compare the D-02 long term experience at 12 months with the D-04 experience at 12 months when we did have that Hamilton rating. Again you see similar rates, three and two percent respectively.

We should not forget that VNS therapy has been on the market for seven years. We have accumulated a lot of safety data from the epilepsy experience, most of which, obviously, is directly relevant to the depression experience also.

As you heard earlier, we now have more than 22,000 implanted patients and over 56,000 patient years of experience. In that experience, we found the VNS implant procedure to be a relatively low risk procedure.

The most important and common adverse associated with the procedure itself are infection necessitating explant in about one percent of patients, nerve damage in about less than half a percent of patients, either in the form of damage to the vagus nerve or the facial nerve, and a phenomenon of transient asystole in the operating room when the device is first turned on for testing that occurs in somewhere between one and two patients in 1,000.

As with the depression data, most of the adverse events in the epilepsy clinical experience and the clinical trials has proved -- most of the adverse events have proved to be minor and stimulation related.

There are few serious simulation related events associated with VNS therapy, and patients -- As a measure of how well tolerated the therapy is, patients in our pool of epilepsy trials continued therapy at a very high rate, about 72 percent after three years.

So in summary, our safety data from the depression studies has shown us that adverse events are mainly stimulation related and not troublesome. There is a low rate of treatment related discontinuation.

There is no signal for treatment related emergence of suicidal ideation or behavior and, obviously, we have to hasten to acknowledge that this is at best a very rare event. So the ability of our dataset to actually detect such a signal would be rather limited, but at least what we can say is, based on the data that we have looked at, there is no signal for emergent suicidal ideation or behavior.

Also data that I didn't show you this morning, another potential adverse event peculiar or specific to depression that we looked at was the rate of emergent mania or hypomania.

About ten percent of the patients in the D-02 and D-04 studies were bipolar patients, and in this group you do worry about the emergence of mania, which can be a side effect either of treatment, and in fact, it is taken by most clinicians to be a sign they have an effective treatment, or it can be due to the underlying disease.

So we looked at that one carefully, too, and we found that the incidence of emergent mania or hypomania was in the range that you would expect for an effective antidepressant. We have data we can show you later, if you are more interested in that.

So overall, VNS therapy was very well tolerated and safe in our clinical trials.

There are also some unique benefits for VNS therapy, as it is a unique approach to treating depression. So from this device based approach, some benefits that you wouldn't get from drugs and, in some cases, from ECT.

For example, Mr. Totah alluded to early in his presentation that patients can acutely disable the device if necessary, to temporarily stop side effects. That is a unique advantage of this therapy.

Also, published data that I didn't present this morning shows that there is an absence of cognitive and psychomotor effects with VNS, and as you have already heard, cognitive and psychomotor effects can be a significant problem with drugs and especially electroconvulsive therapy.

Of course, as a device based approach, there is an absence of overdose toxicity, which is a major problem with antidepressant drugs. Additionally, since it is not a drug therapy, you have the ability to add VNS therapy to other drugs without a concern for a drug-drug interaction.

Not to be overlooked, because VNS doesn't require active participation by the patient in the form of taking a pill every day, treatment compliance is obviously high with this particular therapy. And as you are all aware of, treatment compliance is a major, major problem with all chronic disorders, but particularly psychiatric disorders.

So a lot of patients never get their prescriptions filled. if they get them filled, they don't take them. If they take their pills, they don't take all of them. So this alone, I think, is a significant benefit for VNS therapy.

In conclusion, data that I have shown you this morning shows us that VNS effects on brain structures and neurotransmitters associated with mood regulation provide a biological rationale for the use of VNS therapy in treatment resistant depression.

Adjunctive long term VNS therapy was more effective than a standard of care treatment alone, and the p-value for that was less than 0.001 in the primary analysis.

The differences versus standard of care are not explained by differences in the baseline patient or disease characteristics, concomitant treatments or a placebo effect.

The improvements observed with adjunctive VNS therapy are largely sustained during long term treatment. VNS therapy is well tolerated and safe in depression clinical trials and clinical use in epilepsy, and finally, VNS therapy has additional device related benefits versus standard of care.

At this point I would like to invite Dr. Rush to come back up and just give a few closing remarks, and we will try to put these clinical data into a clinical perspective.

DR. RUSH: Thank you, Richard. I will be very brief. You have had to listen to a long series of presentations.

I want to just address the data and the information from the point of view of a clinician. I have been doing clinical work for 30 years and trial work for the same period of time.

It is important to put into context again, as we tried to do at the beginning, to remind you who it is that we are talking about that we are treating. These individuals, more than half had previously had ECT, and it had not produced a sustained benefit. Many had just not even had a response to it at all.

So these are really the most treatment resistant, the most difficult and disabled depressed patients that I have ever put into a trial anywhere and, as I mentioned earlier, half would not have -- half of the ECT community sample would not be eligible for our study.

To give you a sense of how we recruited patients for this, it might give more of a clinical feel. At least in Dallas, we went out to the well known psychopharmacology masters, if you will, the people that do advanced, complex medication management where treatment resistant patients go.

We asked them each to give us two, your very two worst, most difficult depressed patients. That is how we recruited the patients. So these are really very, very difficult patients for whom we don't have an alternative.

The second question is: Are the clinical effects meaningful? I think, to gauge the value of the clinical effects, you have to keep in mind three things. One is the population itself.

This, as we have discussed, is a population where we really don't have much going, and especially in the long run. So if we can help one in four or one in five to actually achieve a response or better -- and notice that some of our responders actually hit remission, and some of the patients today are in remission -- that is a home run in a patient population where we just don't see it in the long run. It just doesn't happen.

So given the severity of the illness and its treatment resistant nature, and the standard high threshold for benefit, 50 percent, we are looking at 37 percent versus 12 percent using the CGI. So you are looking at a number needed to treat of 4 or a number needed to treat of 5, if you use the Hamilton.

Those are very significant benefits, especially when we are not looking at short term. We are looking at the end of the year, when we should, in fact, have lost territory, if you look at all the other treatments that we have.

We should have done better in the sort run and worse in the long run. In fact, we did not so great on the short run, but really terrifically with this population in the long run. That is the "Duracell bunny keeps on working" for most, not for everybody, as you saw from Dr. Rudolph's presentation, but for most people there is a benefit that largely is sustained at a year.

The good news is some people who aren't benefitted early seem to come up with a benefit later. We have looked at that even over two years, and that seems to be a fact.

Could this really be a placebo? I think, looking at the population just per se, this is so unlikely it would be a miracle to have a placebo of this magnitude that works for this long and that consistently over time. It just would, I think, be looking at it as a clinician, very, very unlikely.

Typically, placebos, when they work, work early. Well, we don't have as much early as we have later. So the timing is all wrong. Secondly, they wear off. Well, we seem to have an increasing benefit over time. That would be a very unique placebo. Finally, those that benefit seem to have a sustained benefit, by and large. That also is unique, would not be easily attributed to placebo.

Finally, the induction of hypomania: While it was an adverse event here, it was more common, as you heard, in bipolar disorder patients. We often look at that clinically in antidepressant trials as an indicator that we have antidepressant activity.

Then finally, we have the experiment in nature, not conducted in any of the D series, but several patients you heard who lost efficacy when their battery ran down and achieved a recapture when the battery was replaced. Not an experiment that we could have done early on, but one that is going on by nature.

Just to put a final face on it and a comment on public health significance. I'll be quiet. I told you about this graduate student at the beginning. That individual entered the VNS study, and he did very well. Within about two months, he achieved remission. So this is unusual. It is one of the earlier responders.

He has stayed in remission now for five years. He finished his graduate school, got married, and has a child.

The other comment I want to make is about the category of response. We are very used to the 50 percent, because it comes from the nontreatment resistant world. Some of the patients mentioned that any benefit to some degree is better than what we have now, and you saw Dr. Rudolph talk a little about the 25 to 49 percent group, and I just want to give you one patient in this regard.

This is a lady who actually was not a responder, but she was a lady who was full time employed, in her mid-forties, married with two children, one just about to graduate from high school. She had had depression, really, since her early twenties, largely on, sometimes off, and the last several years more time -- roughly an eight-year episode, last episode.

She had received 80 ECT treatments. She was in maintenance ECT. She was brought in by her husband who said, the ECT is really helping her; it's the only way we can keep her out of the hospital, but she is having these long term cognitive difficulties and I really -- I can't allow her to go on and she, too, is complaining of it.

So we gave her the VNS treatment. It took a while, probably about three to four months. We kept her medication. So it's past the end of -- Well, at the end of the study, in the three months where medications were fixed, she had a 48 percent reduction in her Hamilton.

Then we followed her out, medications largely fixed. We were very loathe to change medicine. She had been so fragile. She had been in and out of hospital many, many times in the prior several years. So we left her where we were, adjusted the parameters. She never hit response. She never hit a 50 percent reduction. She was always in the forties..

So she comes up as not a beneficiary in the classical definition. Good news is she had been fired from her job because she couldn't function as a computer program or information technology person about a year and a half before we started. She wasn't able to be rehired there. She worked for a large IT company, a famous name you know. But she started a business in her own home and was partially employed.

The most important thing she said was, I got to see my son graduate from high school. Excuse me. So even though we don't call them responders, there are a number of people that actually really do quite well with this. Not perfect, but a lot better than what they had.

Then finally, just let me make one comment about the public health perspective. I did these numbers, and I thought about it, and it's so shocking to me, I thought I would share it with you.

Thirty thousand people per year commit suicide. Eighty percent are due to depression. That is 24,000 people. Treatment resistant depression is known to be the most lethal form of depression. Let's say half of those individuals that commit suicide from depression have treatment resistant depression. That's 12,000 suicides a year. That is 1,000 suicides a month. That is one suicide every 45 minutes. That means we lost four of these individuals in the last two and a half hours due to treatment resistant depression.

This is not a panacea, obviously, but it is a high need and, if we can help one out of five of these people with this treatment, I think it would be a tremendous contribution. Thank you.

CHAIRPERSON BECKER: Thank you. I would like to thank the sponsor for their presentation.

Given the fact that we all have been sitting here for quite some period of time, I think maybe it is appropriate to take a break now and reconvene in 15 minutes, say at ten after eleven. Thank you.

(Whereupon, the foregoing matter went off the record at 10:56 a.m. and went back on the record at 11:14 a.m.)

CHAIRPERSON BECKER: If I could get everyone to take their seats, we'll get the meeting restarted. Alright, thank you. It's now 11:15 and we'll resume the meeting. And we'll start with the FDA presentations on this PMA. The first FDA presenter is Carlos L. Pena, Ph.D. Dr. Pena?

DR. PENA: Good morning panel members. My name is Carlos Pena, and I am here today from FDA to present to you the PMA application for the Vagus Nerve Stimulation Therapy System proposed to treatment of resistant depression. I'm accompanied by Dr. Schlosser, medical officer, who will be sharing with you safety data contained in the application, and Dr. Lao, statistical officer, who will be sharing with you statistical data contained in the application. And I'll be providing the regulatory history of the VNS Therapy System, an overview of VNS studies including efficacy data, and a closing summary.

The sponsor has described the VNS Therapy System in some detail, which includes an implantable pulse generator, lead, and external programming system. The sponsor seeks commercial approval for the injunctive long-term treatment of chronic or recurring 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 antidepressant treatments. VNS has previously been approved for use as an injunctive therapy in reducing seizures in patients refractory to epileptic medications.

Regarding the mechanism of action, no definitive mechanism of action has been reported for the proposed indication for the injunctive long-term treatment of chronic or recurrent depression.

I will now discuss the regulatory history of the VNS Therapy System. Following FDA approval for epilepsy in 1997, anecdotal reports of mood alteration were noted for some epilepsy patients. And the sponsor conducted a 30-patient, later expanded to 60-patient, pilot study called D01. The pilot results led to the development of the D02 study. The D02 pivotal study included an acute, randomized, placebo-controlled phase -- the only randomized placebo-controlled portion involving VNS studies discussed today -- as well as long-term follow-up. The sponsor un-blinded the acute phase of D02 in 2002, and found that the study failed to demonstrate a statistically significant difference between responders in the treatment arm and sham treatment control arm, the study's primary efficacy endpoint.

Despite the failed outcome, the sponsor claimed a pattern of increasing treatment effect over time, and suggested that the full antidepressant effect of VNS therapy might take longer. The sponsor proposed to use a non-significant risk study, D04, as a reference group for comparing to D02, long-term clinical data. And FDA advised the sponsor of the serious concerns regarding the ability of this comparison to demonstrate safety and effectiveness of their device due to lack of a randomized subject data set. The sponsor submitted their application in October of 2003.

In all, there are six studies that will be discussed today. During the first part of FDA's presentation I will focus on the first three studies, called D01:, the pilot study, D02: the pivotal study, and D04: the observation of control study. Other trials include D03 and D06, both of which will be discussed further by Dr. Schlosser, and D05, which was a videotape assessment of D02 study subjects only to ensure interrater reliability in assessments. Which takes us to a description of each study.

In the D01 pilot study, this study was an open label, non-randomized, single treatment arm, multi-center study. The primary efficacy endpoint was the proportion of subjects that responded to therapy, response defined as a 50 percent or more decrease reported as improvement in the HAM-D score at post-treatment compared with the baseline. The HAM-D, the Hamilton Rating Scale for Depression, is a clinician's tool to rate depression.

Out of a total of 71 subjects, 11 discontinued prior to implantation, 60 were implanted, and 59 completed the acute phase. Across various times during the pilot study, several subjects had concomitant treatment changes. Six subjects had changes in concomitant treatments during the four weeks prior to their first visit post-implantation, twelve subjects had changes in concomitant treatments during the acute phase, and three subjects received ECTs during the long-term study, and a total of 77 serious adverse events were reported. And Dr. Schlosser will discuss these events shortly.

At the acute phase exit, 18 of 59 patients were responders, 25 of 55 patients were responders at one year, and 18 of 42 patients were responders at two years. Response defined by a greater than 50 percent decrease in the HAM-D score compared with baseline.

The pilot results led to the development of the D02 pivotal study. And the D02 pivotal study was comprised of two phases, including a randomized controlled 12-week acute phase, and a 12-month follow-up evaluation period. During the randomized controlled acute phase, subjects were required to maintain a stable medication regimen, and during the long-term phase, changes to the mood disorder treatments and ECT were allowed, and no concomitant treatment criteria was provided in the clinical protocol. The primary efficacy endpoint of the acute phase was the proportion of subjects who had greater than a 50 percent decrease in the HAM-D at acute phase exit compared to baseline. And responders in the treatment group were compared to the proportion of responders in the control group.

A total of 266 subjects enrolled, 31 discontinued prior to implantation, leaving 235 patients that were implanted. The second yellow box, green box on the left-hand side. And 222 patients were considered evaluable for efficacy analyses. Of the 222 evaluable subjects, 112 were randomized to treatment and 110 were randomized to sham treatment control. And regarding the long-term phase of enrollment, of the 235 subjects who were implanted, 233 subjects were identified as the safety population, 205 were considered evaluable subjects, and 177 subjects were 12-month completers.

During the acute phase, nine subjects had changes in concomitant treatments and noise to use was reported. During the long-term phase, changes in concomitant treatments were allowed, and 169 patients of the 205 evaluable subjects added or increased antidepressant medications. In addition, 14 subjects received ECT. Of those 14 subjects, eight subjects were 12-month completers, four subjects were categorized as responders, and two subjects were categorized as complete responders. And I would like to remind you that one of our panel questions is related to the use of concomitant antidepressant treatment changes, permissible in the treatment group, over the course of 12 months.

The sponsor reported implantation related adverse events, stimulation related adverse events, and other events from the D02 study. These results will also be discussed by Dr. Schlosser shortly.

The primary efficacy endpoint failed to show a significant difference between treatment subjects, those who received VNS, and sham treatment control subjects, those who received regular care for treatment-resistant depression. In other words, the amount of improvement for patients with VNS was not statistically significantly greater than the amount of improvement when receiving standard care. And other psychiatric measurement tools reported similar outcomes during the acute phase.

Despite the outcome of the acute phase, the sponsor submitted a revised statistical plan with new primary efficacy endpoints, and employed an observational control study for comparison. And the revised statistical plan introduced the D04 control study.

The design of the D04 study was to collect long-term clinical quality of life, productivity, and health care utilization data on patients with depression. The D04 study began towards the end of the D02 study, and was a non-significant risk study conducted under local IRB jurisdiction. Up to 130 patients enrolled, and standard of care was defined in the clinical protocol as whatever treatment strategy the physician and the subject chose to follow.

Which takes us to the D02/D04 comparison. The objective of the D02/D04 comparison was to demonstrate that there is a difference in the improvement of patients with VNS therapy plus treatment compared to treatment as usual. The design, schedule, sample size, concomitant treatments have all been described previously. There was a total of 22 sites enrolling patients in either D02, D04, or both. And of those 22 sites, eight sites enrolled patients for D02 only, and one site enrolled patients for D04 only. And Dr. Lao will discuss statistical outcomes associated with the use of overlapping and non-overlapping investigational sites.

The majority of D04 subjects enrolled after D02 was closed. And sites that enrolled both the D02 and D04 patients usually screened and offered patients enrollment into D02 prior to enrollment into D04, because D02 offered a new treatment as opposed to standard of care, and sites were more focused on the treatment study rather than a naturalistic observational study, D04.

During the six months of overlap between D02 and D04, 83 percent of the patients who met the enrollment criteria for the D02 study enrolled into D02. And 17 patients who met the enrollment criteria for the D04 study enrolled into D04. After D02 closed, clinical sites had a pool of subjects interested in D02 that were also eligible for D04. And subjects that could not enroll in D02 typically enrolled into D04. And I would like to remind you that another panel question you will discuss is related to the enrollment outcomes of an investigational study versus an observational control study.

The primary efficacy endpoint was a repeated measure of linear regression analysis performed on raw IDS-SR scores of D02 and D04 patients. The IDS-SR is a self-assessment tool for depression. And the HAM-D, the primary efficacy assessment tool for D02 during the acute and long-term phase, was only included as a baseline D04 assessment, and therefore was not adequate for D02/D04 comparative analyses.

The D02 study also collected safety data. However, the D04 study did not prospectively or systematically collect any safety data while studying treatment-resistant depression, and is an issue determining whether the VNS Therapy System is safe for the proposed indication.

Evaluable patient baseline demographics between D02 and D04 were for the most part comparable. However, there were significant differences in baseline demographics between D02 and D04, including those patients who received ECT during their lifetimes, patients who received ECT during the current major depressive episode, and patients in the control population with greater than 10 lifetime episodes of depression. In addition, there are several patient variables for which no information was collected, and have been reported in published literature to influence treatment responsiveness. And unmeasured patient variables are also an issue that we have provided as a question for your deliberations later today.

Now, if we turn to the primary analysis comparing long-term outcomes between D02 and D04, a statistically significant difference was observed in the estimated IDS-SR raw scores per month between D02 and D04 at 12 months.

To further evaluate the permissive use of concomitant treatments during the long-term, the sponsor performed a second analysis, not specified in the original or revised clinical protocols, and compensating for concomitant treatment use. Namely, if a subject added or increased antidepressant treatment, and their subsequent IDS-SR scores prior to the change in concomitant treatments, last observation carryforward approach was used. The difference observed in the primary efficacy analysis was not statistically different from improvement observed under standard of care. In other words, there was no improvement difference between patients who improved with VNS and those patients receiving standard of care. And this is another issue that we have posed to you in the form of a panel question.

Aside from the statistical numerical outcomes of one analysis over another, more importantly, the overall permissive use of concomitant treatments during the long-term study is an issue in determining the effectiveness of this device.

And now I'd like to turn the presentation over to Dr. Schlosser, who will be discussing with you the safety data and the PMA.

DR. SCHLOSSER: Good morning. I'm Dr. Michael Schlosser. I'm a medical officer in the division reviewing this device. And I'm going to briefly talk about some of the safety data and the PMA.

I'm going to start by clarifying some of the terms. The sponsor purported the data, the safety data, looking at adverse events, and then also looking at treatment-emergent or stimulation related adverse events. And so I'm going to talk about those two categories. And then as a third category there were these serious adverse events. And so, throughout the slides I'm going to be talking about each of those three different groups, and I'll try to explain exactly which group we're looking at at the time.

Because a lot of the events we're talking about were stimulation related adverse events, I wanted to talk briefly about the stimulation parameters that were used in the protocol, just to start with. Specifically, I'm just going to focus on the current output. Current output was limited to 0.25 to 3.5 milliamps by protocol in the IDE. The adjustment protocol called for increasing this output by 0.25 milliamps in steps until a maximum tolerable level was achieved. Programmers were specifically instructed to warn patients that higher level of stimulation and stimulation related adverse events did not necessarily correspond to higher efficacy. In the protocol, it was listed that this was based on experience with the epilepsy patients, and therefore the programmers were instructed to tell the patients not to tolerate events that they really would normally not tolerate because they thought it was going to improve their efficacy.

Stimulation was to be decreased any time a patient reported that there was a painful or troubling adverse event. And the programmers were instructed to continue to increase the current during the programming phase in order to try to reach that maximum tolerable level during the two-week programming phase of the acute phase of the study. It was also noted in the protocol, and in the instructions to the programmers that any individual patient may have very different responses to different current levels, and they even went as far as to say that there may be some patients for who 0.25 milliamps would be the maximum tolerable setting, and that that should be expected and not an area of concern.

In April, 2005, Cyberonics sent a letter to the D02 investigators instructing a new stimulation protocol. This was to be implemented in patients who had a HAM-D score of greater than 10, which was their definition for non-responders at that point in the chronic study. This protocol specified a ramp-up period of six weeks during which, and this is a quote from the letter, several attempts should be made to increase output current to a level of 1.5 milliamps. It was also recommended that patients undergoing the ramp-up procedure be seen more frequently, every two weeks, but as frequently as every week, during the ramp-up period. And it was additionally recommended that if patients couldn't tolerate 1.5 milliamps, that an adjustment be made to -- I'm sorry, an adjustment be made to the pulse width in order to decrease it to 250 milliseconds, which may facilitate an increase in current levels.

So, now moving more specifically to the safety data. I'm just going to go through the different studies that we've already heard about this morning and talk about the safety data presented for each. There were 60 subjects in D01. Every subject reported at least one adverse event. The most common adverse events, which were reported in at least 10 subjects, were device site pain, headache, incisional pain, neck pain, dysphasia, increased cough, dyspnea, and voice alteration. These are kind of the common adverse events that we're going to see though the rest of the slides. They're also similar to the events known to occur during stimulation in epilepsy patients.

There were 77 serious adverse events reported across 38 of the patients. So greater than 50 percent of the patients had a serious adverse event. The most common being 12 suicide attempts or overdose events, and 34 cases of worsening depression. These are incidences of events, not number of patients. There was one death as a complication of surgery due to rectal prolapse.

In the acute study, now looking just at the acute D02 phase, 235 implanted patients. There were 233 reporting an adverse event. So, again, nearly every patient reporting adverse events. The events were classified in the PMA as mild, moderate, or severe. Mild was defined as easily tolerated and transient. Moderate as caused discomfort and interrupted usual activities. And severe, considerable interference with usual activities.

As you can see, there was a very large number of adverse events in both groups. It's important that we obviously look at the adverse events in both of these groups since they both had the surgical procedure and the implant. They were both exposed to risk. There was 61 severe adverse events in the treatment group and 73 severe adverse events in the sham control group. The difference between the adverse event rates to the treatment in sham control group probably relates to stimulation related adverse events, which I'm going to come to.

This is now just looking, again, at just all adverse events in the D02 acute phase. So these are not graded in any way as to their relationship to the device or to stimulation. And we can see the most common adverse event was clearly voice alteration, which was very common. Eighty-one patients, 68 percent of the treatment group; 44 patients, 37 percent in the sham control group. And then again, these are those adverse events that I read in that first slide that are going to be the ones we're going to see over and over again: device site reaction, device site pain, incisional pain, dysphasia, incision site reaction, cough, dyspnea. Similar events that you would expect given the direct stimulation to the Vagus nerve.

This slide now kind of focuses in a little bit on events. These are treatment-emergent adverse events that were rated as possibly, probably, or definitely related to stimulation. So this was a cut made by the investigators in the study. When they reported the events, they would then report whether they thought the event was related to stimulation. So you can see, it's the same type of list. It's really the same adverse events. There are very few of these events listed in the sham control group, which makes sense because these were events that the investigators determined were related to stimulation. So it's obvious that the investigators were able to pick up which events were related to stimulation and which patients weren't getting stimulation.

We've heard this morning that these events are similar in their frequency and in their nature to the events seen in the epilepsy study. I'm going to come back to that in one of my last slides. But I'll just make the point at this point that in this situation, we're comparing the adverse events and risks seen in patients with depression, to the benefit of this device in depression. And the safety of the device in another population doesn't necessarily mean that that device is safe in this different population. And the risk/benefit ratio must be looked at separately.

Moving on to serious adverse events. Just as a reminder, the definition of a serious adverse event is an event that resulted in death, a life-threatening event, hospitalization, prolongation of a current hospitalization, or a persistent disability. There were 39 such events. Nine occurred prior to implantation in the acute phase. So there were a total of 30 adverse events occurring between implantation and acute phase exit, 16 in the treatment control group and 14 in the sham control group.

If we look at these events individually, again, we have the most common is depression. I'm going to mention some things about the depression as an adverse event in a study of depression in another slide. But that was the most common serious adverse event. There was one suicide in the treatment group, none in the sham group. There were two cardiac events of note, an asystole and a bradycardia, both of which rose to the level of a serious adverse event. And then one wound infection. And then you can just go down the list, noticing that these numbers are small and there's one or two patients on either side. So there really are no statistical differences to be examined between treatment and sham control groups. And again, both groups were exposed to the device, and so, really, adverse events in both groups should really be included in the safety profile.

If we look now at the chronic phase of the D02 study, again, this is just serious adverse events. We see seven suicide attempts in six patients, four episodes of syncope in three patients, and then gastrointestinal disorder, convulsion, one episode of sudden death. I'm going to come back to sudden death at the end. And then by far and away the most common reported serious adverse event in the chronic phase was depression, 62 instances in 31 patients. The sponsor in the PMA explains that this probably represents a lack of efficacy of device rather than a true adverse event of the device.

Moving on to the D03 study. We haven't looked at the D03 study in the FDA presentation yet, so I'm just going to review the clinical protocol quickly. This was an open label, non-randomized, single arm, longitudinal study. It's the post-market study in Europe. It actually began before the CE mark, but the majority of the study has actually occurred afterwards. So it became a post-marketing study. Antidepressant treatment changes were allowed in this study, and the primary efficacy endpoint was a portion of subjects with a 50 percent response on the Hamilton rating scale at 12 weeks compared to baseline.

Safety data was collected in this study, and provided to us. Looking at just, again, the serious adverse events, 47 subjects implanted, 14 serious adverse events in those 47 subjects. Again, the most common, four cases of worsening depression. There were two suicides, which were also the only two deaths in the study. And then down the list, bacterial infection, accidental overdose, accidental injury, one case of syncope, and then gallstones, kidney stones, and kidney pain.

I won't go over specifically what the stimulation related non-serious adverse events were for D03. But as per the sponsor's submission, they were similar to those seen in D02 and D01 and in epilepsy studies.

The D06 clinical protocol. This was a pilot study of safety and efficacy in rapid cycling bipolar, as we heard. Standard bipolar disorder patients were included in D02, but rapid cycling patients were not. This was a separate study looking at that population by itself. It was again an open label, non-randomized, single arm study, so it was not designed to be an efficacy study, but did collect safety data, which we have. There were 11 subjects enrolled. Only seven actually implanted. And two subjects had one-year follow-up only, so we don't really have long follow-up on these patients.

We do have safety results. Again, I'm focused on serious adverse events. There was one suicide, three suicide attempts, one prior to implantation, two cases of worsening depression, and one case of manic reaction. So seven events in seven patients, though two subjects reported two events each.

Now we heard this morning about the specific focus on suicide. Obviously, published literature and recent experience has taught us that in very rare cases, antidepressant medications can precipitate suicidal behavior. There were 12 suicide attempts or overdoses in D01. The D02 acute phase had one suicide in the treatment group, none in the control. The long-term phase of D02 had seven suicide attempts in six patients. That was by the cutoff date for submission of the PMA. Since then there have been two more attempts in two additional patients. D03 study had two suicides. We don't have the report of attempts. And D06 had one suicide and two attempts in seven patients. So enough to make us concerned that there might be something to precipitation of suicide by this device, or at least to look at it more carefully. Again, a reminder that safety data was not collected in D04 for comparison.

This is kind of a busy slide, but what we're looking at here is the D02 acute phase on the top, and then comparative data, which includes a combined D01, D02, and D03 group on the bottom. So treatment group versus sham control group. Very small n here, only one suicide in the treatment group, none in the sham group, and no attempts. So tough to make a comparison, though, 4.3 percent versus zero percent. But the numbers are small.

In the larger comparative data we're looking now at a larger group, 342 patients in the combined analysis. And we see, as the sponsor showed this morning, if we look at instances of suicide per year, 0.4 percent. This is, again, comparison to this Khan Study, which was this very large meta-analysis of drug studies used for approval. And there we had a 0.8 percent rate in the treatment group, and a 0.4 percent rate in the placebo group. So similar numbers of instances of suicides per year and suicide attempts per year between the D01, D02, D03 combined and the meta-analysis.

Now, I mentioned I would come back to the epilepsy data. This is a chart that represents the stimulation related adverse events in the E-O5 study, which was the pivotal study for VNS for treatment of epilepsy. And again, you see this very similar list of adverse events that we've seen on all the previous slides: cough, dyspnea, hoarseness and voice alteration being the common events. This was a comparison between baseline and then high levels of stimulation. So these are actually patients compared to themselves. And we see, you know, they all reach levels of statistical significance. So these are all adverse events that are related to the stimulation, and they can be bothersome to the patient.

But again, I'll just restate that the determination of safety is not done in a vacuum. It's done as a risk/benefit analysis, comparing to the benefit or the efficacy of the device. And so the safety in the epilepsy population does not necessarily mean safety in the depression population. The adverse events must be weighed in relationship to the benefit shown by the efficacy studies.

And then finally I'm just going to finish by talking about cardiovascular events. I mentioned the one sudden death in the D02 study. There were also, I believe, two cases of sudden death in the epilepsy studies, and cases reported in the MDRs as well, very rare incidence of sudden death. There is a concern that this might be due to cardiac events due to the direct vagal nerve stimulation. Could this be causing a cardiac event that led to sudden death?

So we looked just kind of specifically at what cardiovascular events were seen. The events in red are the serious adverse events. This whole column is in red, even the zeroes, because I have not included the non-serious adverse events for the chronic phase. There were many, and in many cases they were the same patient reporting the same adverse event at each visit. For example, bradycardia. But there was no action taken. There was no action needed. And so those numbers were very large, but not necessarily meaningful. So the serious adverse events in the chronic phase: four cases of syncope, one case of dizziness. And then when we look at the acute phase, the case of asystole and bradycardia which I've already mentioned, and then several other cases of arrhythmia, hypertension, 10 cases of palpitation, 21 cases of dizziness. I should mention that of course there are many causes for dizziness, so while we lump this under cardiovascular events, there obviously can be other reasons why people can be dizzy. Vasodilatation and syncope.

So there were cardiac events. We don't have any evidence of sudden death due to a cardiac event from vagal nerve stimulation, but it's just something to keep in mind in terms of the safety profile of the device.

Now I'm going to turn it back over to Dr. Pena for a review.

DR. PENA: So in review, regarding safety, the absence of systematically collected safety data in the observational control study for comparison to the investigational study is an issue in determining whether the clinical data in the PMA provides reasonable assurance that the device is safe for the proposed indication.

And regarding efficacy, FDA has identified the following issues, including first, the chief limitation that the long-term D02/D04 comparative analysis is not derived from a randomized subject data set, but rather a comparison of outcomes from an investigational device study and observational control study. And a propensity adjustment strategy used to reduce potential bias in the comparative analysis is not able to address the problems of potential bias due to other unmeasured patient variables.

I would also mention that the sponsor noted in correspondence to FDA that both the D02 and D04 population would not differ on measured factors upon submitting their revised analysis, and that if they did, one could not be as confident in their statistical adjustment for baseline differences. FDA's uncertain whether one can reconcile the sponsor's statement in their own submission concerning there were relevant measured patient variables found to be significantly different between groups.

Second, FDA's concerned with the potential placebo effect rates for patients with VNS. The sponsor has discussed in some detail reasons why long-term outcomes from VNS patients are not due to placebo. Data provided in the submission identifies a placebo response rate of 10 percent, as defined by the clinician's measurement scale HAM-D, which persisted to the exit of the acute phase, namely 12 weeks.

Also, although both D02 and D04 were available to enrolled subjects at similar time periods, almost all D04 subjects enrolled into the study after D02 was closed for enrollment. Only 10 D04 subjects enrolled into D04 while D02 was open. And the sponsor has indicated that sites were more focused on the treatment study rather than the naturalistic observational control study.

And third, moving past the insignificant numerical outcomes upon censoring scores of VNS patients with concomitant treatments, and using their last observation carried forward, FDA is concerned that concomitant medications an ECT use were not standardized in either the D02 long-term study or the D04 observational control study. And I would also mention that when a patient adds or increases treatment, one can reasonably expect that patients are not responding, or poorly responding to their current therapy regimen. And one would be unsure of the cause of the patient's improvement to subsequent additions or increases in antidepressant treatments.

At this time, I would now like to turn it over to Dr. Lao, who will be presenting the statistical data contained in the PMA submission.

DR. LAO: Good morning, my name is Chang Lao, Division of Biostatistics, FDA. Today I am going to present a comparison between D02 and D04. D02 is the VNS plus standard care. D04 is standard care only. And the primary/secondary efficacy endpoint is HRSD-24, is the Hamilton Rating Scale for depression, 24 items. Maximum score 74. IDS-SR is maximum 84.

In the multi-center study, 22 sites, and overlapping Site 12. I'm going to talk overlapping sites later on. And then talk about propensity score analysis, try to test covariates in pairings. And then repeat a measure in the concordance study, try to predict an HRSD from IDS-SR. Then there is a statistical conclusion.

This is a D02, a brief summary on all 22 sites combined. In the three-month actual study, which is double-blind, randomized, VNS was a sham control. Primary HRSD, parameter, and IDSS-SR is secondary. And primary endpoint is the comparison to response proportion. The final result based on three-month actual study, the significant difference was found for the IDSS-SR, which is 17 percent, VNS was 7.5 percent sham, 0.03 based on psych test. No significant differences were found for the HRSD.

Then after three months, every patient was switched into VNS. So the primary endpoint for D02 only is HRSD. Try to estimate a slope for every radar change, scope must -- we try to estimate a mean response score when you study. The slope average amounts of change in HR score 0.45 per month. Which is standard endpoint of 0.05/95 company's interval.

D02 and D04, long-term comparison, the endpoint is average rate of change, which is slope estimate average mean score per quarter by repeated measure and integration. And the longitudinal data for the HRSD, D02 yes, D04 no. Because it only had a baseline and 12 months data only. So the sponsor switches to IDSS now because they had both longitudinal data. And to do the repeated measure of lineal regression.

Secondary endpoints is a proportional response based on the 50 percent reduction in score from baseline. This is a sample size table for the -- all the 22 sites, overlapping sites. Overlapping site means some site had both D02 and D04. As you can see, this sample size here, in the overlapping site the sample size is much smaller than the other 22 sites combined. By the way, sample size was based on the secondary endpoint. Compare the proportion of the response between the two groups. Not based on the primary endpoint.

This chart illustrates the patient by study and center for the D02 and D04 comparison. As you can see, about nine sites which had a D02, but no D04 study, and one site had D04 and no D02 studies. So overall, 10 sites out of 22 sites, which are roughly about 45 percent, no comparison group for those sites. The study design is incomplete and unbalanced. And it's hard to evaluate a true homogenous cross center. A true center interaction effect cannot be evaluated.

Propensity score analysis, which is when you have many, many confounding covariates present. Then the propensity score actually is overall composite scalar, sure to intend to reduce by comparison between D02 and D04. It took the best covariate only. Propensity score is a condition of probability of individual patients receiving D02. Condition even a set of IS patients, of best covariate, XI. We have total 17 covariates. Before after propensity score adjustment, use of logistic regression, which is a logit. Logit is a proportion of success to no success, probability of no success. Logit, log of that, actually is a probability assigned to D02 conditioned on a set of covariates. Vector X for the IS patient. The furnishing of the vector for a covariate for IS patient. So some basis of logistic regression.

Primary effectiveness analysis and repeated measure analysis, which its purpose is to estimate every radar change per month, or to estimate the mean response at 12 months, which is general mean response mode. We are interested in only comparing the mean, scope, from baseline between D02, D04, at 12 months, not individual patients performance, which were required for random effect mode. So the dependent variable here, IDSS, independent variable is the baseline IDSS-SR, treatment in either D02 or D04, or time, four quarters. And the PS quantum five level group by the Propensity Scale for each individual patient. Nine pool sites from 22 sites. And measured by time interaction and the special power correlation which allowed the correlation to change over time. And so missing random. Probably we are missing data in future. All absent data is independent, missing data independent from the future of this issue. Next.

Concordance study shows how good are the ideas of particular HRSD. And the statistics uses a correlation of linear regression. Outcome is a correlation coefficient intercept slope R-square. R-square is a percent variable, about a mean of HRSD, explained by the future regression model. How much can explain by the independent variable, IDS-SR?

A range of R squares, zero to one. Zero is the worst fate. One is perfect fate. So if R squared equals one, that means the IDSS-SR can predict HR very well. If zero, then no prediction at all.

This is a value, the top number is the repeated measure linear regression result. All the 22 sites combined. And top of the graph, the number there is each quarter observed predictive value of mean score, at each quarter for D02 and D04. At the bottom of the chart, there, you see the difference. D02 minus D04, observed at -6.6, which is not adjusted for any patient covariate, individual patient baseline data, or propensity score.

The predicted value after one year is minus 4.8, which is a reduced improvement at one year. This is for all 22 sites combined. If we look only for the 12 overlapping sites, the 12 have both D02 and D04. Then the improvement, at the bottom of the chart you can see that at one year, the improvement -- difference about 1.4 points. And the 95 confidence even before that difference, D02 minus D04, minus 3.82, minus 0.5. That's based on 12 overlapping sites.

This is a result for the concordance study, as I talked before. R-square, the position of R-square by this histogram. You would like to see the R-square equal close to one as possible best prediction. If close to zero, no prediction at all. The mean of this distribution of 235 evaluable patients, D02 study, of 0.55. Which means about 55 percent variability, and above the mean of the HRSD data, explained by IDSS-SR. So I would say it is, R-square is kind of in the middle. So concordance study, also you can look at the correlation coefficient and the slope. The mean correlation is about 0.70. And undefined of 0.67 to 0.73. And the slope, we use the average rate of change for the HRSD, for every unit change of IDS-SR.

Second endpoint is a definition of IDS-SR or HRSD score larger than 50 percent reduction from baseline. Statistics have several concerns here. Treat it like all the 22 sites as one site because the sponsor combined all the responses and non-response by D02, D04, combined together from those 22 sites. So it looks like the data all comes from one site. So no treatment in the baseline interaction was considered here. And supposed to talk about logistic regression for the response rate comparison to response proportion. But I don't see it. The covariate only appear in the linear regression analysis. So no pooling of the data, no modern approach, no covariate adjustment, like a baseline IDSS or HRSD site ECT RX used.

One reminder. IDSS is a baseline which was highly significant in the repeated measure regression. And also pool site is highly significant. So the unclear why to compare two proportion responses.

Summary. Three months double-blind randomized provided most for VNS. You know, this provisional study kind of weak in variable patients, all 22 sites. HRSD and the PY 0.3 second IDS-SR, which is 0.039 second. Based on two-sided extract test.

So the switch from primary HR to the two second endpoints, IDS-SR, in long-term study. Summary. In a way, the D02/D04 study is non-randomized, un-blinded. Propensity score were used for balance of a measured covariate only. Approximately the balance seemed to have achieved. Look at the difference of propensity score between the D02 and D04. Reasonable balance in PS quintiles. PS balance individual patient covariate, which is good. But, PS propensity score cannot balance unmeasured covariates selected by -- not accounted for by covariate, regression to the mean providing a placebo effect.

Summary. Data one can follow. If antidepressant resistant ratings score increased, and/or ECT was applied, the prior IDS-SR HRSD score was carried forward to the place subsequent. Now we're missing observation. Unclear effect of analysis in preparation of these for censored analysis, which we based on definition above. It's kind of not easy.

Now, over to D02/D04 site. Nine sites they had at D02, one site at D04. No D04. Only 12. Reduce the sample size by one-third. PS used nine pooled sites in the repeated measure. So it only partly accounts for the imbalance. And also used only 12 over the sites. Show a last effect.

This is the difference D02/D04 in repeated measure regression for IDS after one year. We have different end result here. Covariate -- observe just for covariate, based on raw data. The average difference after one year, about 6.6. Ninety-five confidence interval, about -10 to the -3.2. And it's just by covariate. All the 22 sites are about 4.8, with a 95 confidence interval. But if we use the overlapping site, we censor data. Then implement only cut it down to 2.1 points. And the 95 confidence interval minus 3.842, minus 0.54.

Always think of the 95 confidence interval rather than P value is more meaningful. Because P value only tests low hypothesis. The true difference equals zero. Equals zero doesn't equivalent -- may not be equivalent to the true clinical difference.

Summary. Unclear concordance study. Ask why 235 patients, about 0.55, which is kind of, you know, it's hard to say. It is not perfect predictor, anyway. And the way we estimate a mean difference IDS-SR, D02 minus D04, minus 2.1 unit to 4.8 unit, depending on which data you use, minus 2.1 with baseline of 12 overlapping sites of 4.8 points with all 22 sites. This improvement is clinically meaningful.

So this is based on the second endpoint, based on 12 months proportion of response based on 12 overlapping sites only. The only significant difference for the nine site data and all the 22 sites was 0.001. The main comparison source of data for the 12 overlapping sites didn't show any significant difference between the D02 and D04, for the second endpoint.

This ends my talk. Thank you.

DR. PENA: Panel members. The management of treatment-resistant depression is a therapeutic challenge to clinicians, and many such patients continue to lack adequate treatment options. However, any proposed device would need to have balanced scientific evidence to establish reasonable assurance of the safety and effectiveness of its use. Thus FDA has drafted five panel questions for your discussions in the afternoon session. At this time, FDA has completed its presentation, and we wait for instructions by the chairperson.

CHAIRPERSON BECKER: Thank you. We have about 45 minutes until the lunch break, so I think I'd like to open the session up for questions by the panel to the FDA presenters initially. Does anybody on the panel have a question for the FDA presenters?

DR. ELLENBERG: Yes, I wonder if you would mind bringing up the slide again for the covariate adjustment. I believe it was the third from the end in the statistical analysis. I'm afraid I didn't understand the presentation.

DR. PENA: Which slide did you refer to?

DR. ELLENBERG: It's the third from the end. It's titled Difference D02 minus D04 in IDS-SR improvement by one year.

DR. LAO: If you don't observe -- it's just based on observed only. And the sponsor's presentation shows after one year the difference, about 6.6 point difference with 95 confidence interval -10 to the -3.2. That's didn't use any statistics, just use the raw data, observed data. But --

DR. ELLENBERG: So that is not with any propensity score adjustment? Is that what you're saying, that's the first row?

DR. LAO: Yes. You are right.

DR. ELLENBERG: And then the second row is?

DR. LAO: Use the repeated measure linear regression, which use the propensity score adjustment. Also, individual patients' IDS-SR score. And the ninth --

DR. ELLENBERG: Wait, wait. So the second one is -- they're both done through the IDS-SR?

DR. LAO: Yes.

DR. ELLENBERG: Both rows?

DR. LAO: Yes.

DR. ELLENBERG: Alright. And the second row includes the PS adjustment. I believe the sponsor indicated that in the linear regression modeling, that the propensity score adjustment was not significant.

DR. LAO: That's right.

DR. ELLENBERG: Is that clear? Okay. So, in the second row you are presenting this data, and you're doing it for all 22 sites, and then for the 12 sites that are overlapping.

DR. LAO: Yes.

DR. ELLENBERG: So you give two results. And what is the point you're making?

DR. LAO: Making is because total 22 site. Ten site incomplete, missing, that didn't have the both D02/D04 study. So there's no comparison can be made for those 10 sites. So I would think you're using 12 sites which you had both D02/D04 study can do a meaningful comparison with each site.

DR. ELLENBERG: So you believe that using the overlapping sites only is a more legitimate comparison than 22 sites?

DR. LAO: Yes.

DR. ELLENBERG: Okay. I understand that. And then, in terms of differences between what the sponsor presented on the first row and what you're showing for the 12 overlapping sites, they're both below zero. The confidence interval are both below zero. So, are you making a claim that there is a difference in the differences here?

DR. LAO: You have some difference here. But the confidence interval leaves some clinical decision here.

DR. ELLENBERG: Right. So you're just stating that the company's interval is different from the interval you get with the 12 overlapping sites.

DR. LAO: Yes.

DR. ELLENBERG: And also -- I'm not sure why that's important if the propensity score wasn't statistically significant.

DR. LAO: The propensity score is only one of the covariates used in the linear regression. There are some other nine pooled sites, or individual IDS-SR baseline data which is highly significant.

DR. ELLENBERG: I'm sorry, I'm not following that at all. Start again?

DR. LAO: Patient baseline data, IDS-SR.

DR. ELLENBERG: That was not included in the propensity score?

DR. LAO: That was included in the repeated measure linear regression.

DR. ELLENBERG: In addition to the propensity score?

DR. LAO: Yes. Yes.

DR. ELLENBERG: And so this analysis with the 12 overlapping sites includes those baseline scores?

DR. LAO: Yes.

DR. ELLENBERG: And the first row for the sponsor submission did not include those covariate baseline scores?

DR. LAO: First row -6.6 didn't use any covariate adjustment, didn't use any repeated measure linear regression, just --

DR. ELLENBERG: Okay, thank you. I understand.

CHAIRPERSON BECKER: Are there any other questions for the FDA presenters?

DR. ELLENBERG: Yes, I'm sorry. An additional question. Another statistical question. Can you explain to panel why it's important that if you're using all of the sites in an analysis as was done by the sponsor, you thereby, since you don't have complete overlap, are eliminating the possibility of looking at any differences in the results by site. In other words, the more technical term, the site by treatment interaction can't be estimated.

Can you explain to the panel why for this particular PMA looking at the site by interaction would be extremely important, moderately important, very important. Are their hints in what you've seen in the data that it's really critical to look at the site by treatment interaction, or are you just making a statement that one always looks at the site by treatment interaction because there may be differences and we would want to see that?

DR. LAO: The idea that you would like to see the treatment effect D02 minus D04 difference is homogenous across center. So then you can try to use the statistical model to pool data, get overall evidence, summary evidence from all the sites. But if you have the 10 sites without a comparison group then the statistical model would be very difficult to the pooling of the data.

DR. ELLENBERG: I understand that, but is there something in the data that you've seen for what the D02 minus D04 difference is looking at them by site that would hint to you that this is something we should be concerned with?

DR. LAO: Yes. Hopefully they go the same direction. D02 is always superior to D04 for most of the sites. Not necessarily for all the sites, but for most of the sites. If you see the opposite direction, if you saw within some site D04 superior than D02, or other way around, then you wonder is it a correlative interaction there. You wonder how can you combine the data. Is something going on there that's not only due to treatment effect, maybe due to site effect.

DR. ELLENBERG: But are you presenting a hypothetical, or are you seeing the data in a way that indicates --

DR. LAO: No, I didn't see the data.

DR. ELLENBERG: Alright, so let me restate what I think your point is. In general, there could be an interaction between the treatment and the sites, which in lay terms simply means that the treatment effect might be different by sites. The treatment effect could be different by sites in two major ways. One way is that it's -- the treatment effect is considerably less in some sites than in other sites. Another way is that the treatment effect is entirely different in some sites than other sites. So it's useful to, at a minimum, review the site differences, and at a maximum be able to model through using a technical term, an interaction term, in the model. But there's no evidence that you've seen from the data that indicates that there is a treatment by site interaction of either sort. Has that made your point correctly?

DR. LAO: Yes, you are right.

DR. ELLENBERG: Thank you.

DR. LAO: The difficult point is here this is not a randomized trial. So the sample size for some sites is very small. You really cannot make a meaningful comparison for those sites with small sample size. Not enough power.

CHAIRPERSON BECKER: There's another question for the FDA presenters. Dr. Wang?

DR. WANG: What I'm interested in is your possible reasons for that discrepancy in the acute phase D02 results depending on which measure is used. Maybe actually if you can go back to Dr. Lao's slide, it's the one, D02 Brief Summary. It shows the acute phase results. There it is. What's your -- you've shown us that the correlation is moderate at best between the HAM-D and the IDS. What is your suggestion here? Is it that the -- someone suggested the IDS is maybe a more relevant modern measure of the depression constructs. Or potentially this is a self-report measure and you could imagine maybe being more prone to bias or a placebo effect? What's your sort of reasoning here?

DR. PENA: Well, we have concerns regarding the various psychometric tools that were used to measure effectiveness during the acute phase. So, while the IDS-SR demonstrates statistical significance between the viable patient population, there were other psychometric measurement tools that did not demonstrate statistical significance. So that makes us wonder if the outcomes, really how strong those outcomes are across different measurement tools.

Some of those measurement tools include the HAM-D, the BDI, the SF-36, and the MADRS, Montgomery Ashberg Depression Rating Scale.

DR. WANG: What is your sort of suggested or proposed weakness of the IDS-SR?

DR. PENA: Well, you would want -- we haven't arrived at a conclusion. We have serious concerns, though, with only one scale able to demonstrate statistical significance in acute phase period.

DR. LAO: If you look at the histogram for the R-square, the prediction varies from patient to patient. That's the point there. Some patients predict very well. Some patients no prediction at all.

DR. PENA: I'd just like to add one comment. And it's one of the reserve slides that we do have. During the acute phase, in both the treatment group and the sham treatment control group, there were four subjects that were categorized as a responder, but neither were in either the HAM-D or the IDS-SR. They were responders in one, not the other. So it's further concerns regarding the concordance and the outcomes of one tool over another, and the strength of the data.

DR. WITTEN: I think you also might want to note that it's not -- there's not the same totals. If you look at the slide that you were referring to for Dr. Lao, there's not the same total of patients. It's a relatively small number that aren't in both groups. But it's a small number that's a difference. Numerically, they were successful in both groups.

DR. WANG: The non-responders might be an extreme.

CHAIRPERSON BECKER: Any further questions for the FDA? Dr. Malone?

DR. MALONE: On the D02 acute, I think you did have a slide that said it was a failed study because the primary efficacy measure was not met? Is that right?

DR. PENA: Right. The acute phase data, the outcome of that acute phase failed to reach its primary efficacy endpoint. So it failed to reach that prospective outcome.

DR. MALONE: So my understanding would be if you want to do all these other tests, you have to start doing corrections for them. Because you're doing multiple tests. I mean, but regardless of that, it's a failed study. Is that right? If you take the primary outcome measure?

DR. PENA: Correct.

CHAIRPERSON BECKER: If there are no further questions for the FDS, perhaps we can start taking some questions for the sponsor at this time before we break for lunch.

Actually, I'll get things rolling by just asking a very simplistic question. If the sponsor wants to take the table. I was wondering how you chose the 12-week time frame for the acute study, which seemed not to be effective, but in the long term it was. Why did you initially choose that acute time frame? And when you saw that the study was negative, why didn't you continue in a randomized sham controlled fashion?

DR. RUDOLPH: The 12-week period is pretty standard for a drug trial. So we were following the pattern that's been used for drug trials. They're typically nowadays eight to twelve weeks. So that's the explanation for why it was set up that way initially.

I think the second part of your question was why didn't you just extend that longer. Well, by the time of course we un-blinded the results for that acute phase, the patients were all beyond the acute phase, so there wasn't an opportunity to continue it as a double-blind randomized trial.

CHAIRPERSON BECKER: There wasn't the opportunity just to continue stimulating one group and not stimulating the other group?

DR. RUDOLPH: Well, by the time that we saw the results, the sham treatment patients had already crossed over into the continuation long-term VNS stimulation.

CHAIRPERSON BECKER: Okay. Further questions for the sponsor?

DR. ELLENBERG: Yes, if I may. In reviewing the material and in hearing the superb presentations today by the sponsor, it seems to me that the analyses that have been presented in detail make every attempt to cover the issue of potential bias in making comparisons between one group of patients who have the essentially standard of care plus the VNS versus another group of patients who had basically equivalent standard of care. But patients that based on the FDA testimony just finished might not overlap totally in time, patients that might not be coming from the same centers, and most importantly patients that were not randomized to the two treatment arms.

At the end of the day, I wonder if you could respond to a reasonably direct question, whether the analyses that you have presented today make the presentation and our job in terms of making a recommendation to FDA based on a non-randomized comparison an okay decision. Can you try and help me to understand why there is not a need to do a new randomized study to make this comparison based on the initial findings, which looked extremely promising, especially after all the analyses that you presented today. Can you just help at least me, if not the rest of the panel, in arguing the case?

DR. RUDOLPH: Certainly.

DR. ELLENBERG: Thank you.

DR. RUDOLPH: One of the very first things we did when we saw the results and understood the results from the acute study was consider the possibility of doing another study. Ultimately we decided that the use of the D04 group as a control would give -- could potentially give high confidence in a determination of effectiveness. But we were also influenced by the fact that every other study design that we envisioned and discussed, both internally and with external consultants such as Dr. Rush, had significant limitations. And Dr. Rush can walk you through some of our concerns about doing another study.

DR. RUSH: Could I have the slide up, please? Let me try to take you through the thinking in the pattern, because the timing is very relevant here. Obviously it would be wonderful to have a randomized control trial. We began the entire evaluation of VNS in depression at a time when there, in fact, were no short or long-term randomized control trials in TRD short of acute trials with ECT that a few investigators had conducted. In fact, the natural course of TRD had not been mapped out by anyone, under routine treatment conditions for a 12-month period. And of course there was no long-term safety. In fact, in the initial study there as no short-term safety of Vagus nerve stimulation in depressed patients at all.

So the plan, which you saw as the D02 trial, was to conduct based on the epilepsy model. Part of the reason for the 10 weeks was the epilepsy model. It was an acute trial, 10 weeks long, following two weeks recovery after implantation, and it would compare sham versus VNS with very tight controls. So no medication changes within that three-month period. If you found a positive difference between the two groups, you could uniquely and absolutely attribute cause to VNS, and that would be the best evidence for efficacy. Even if it were modest in the short run, you could say it was the VNS.

And then the plan actually agreed to with the FDA was that there would be a long-term uncontrolled follow-up of a significant number of people who had had VNS to see whether or not there was a sustained benefit which would be extremely unusual in treatment-resistant depressed patients, as I showed you from the data this morning. So that was the plan. And the reason for it was simple, it's direct, has minimal patient exposure, long-term safety could be established. It's the most efficient path to approval, and it just made a lot of sense. And we had already done the D01 open trial to indicate that in fact there was a reasonable chance of a reasonably good benefit in the 10-week time period.

So as you know, the results, the primary outcome failed the positive finding on the secondary outcome. Then the question obviously is raised, gee, was the sample size too small? Well, I guess if it had been made larger we might have achieved a difference in the primary outcome. And what about a longer duration, a subject you already raised.

So as Dr. Rudolph said, at the end of that trial period, we couldn't then go back. The trial had already shut down. So, next slide. We then considered a variety of next-step options. One is to just simply conduct a longer term acute trial. Let's go out nine to twelve months. You have now maximized the duration, and if you don't change the medications, you can attribute with absolute certainty cause to VNS. It's a terrific design except it's not feasible, it's not ethical, and it's not safe. And you couldn't have any patients sign up for it. Because these are treatment-resistant depressed patients. The number of medication changes that occur over even a six-month period just to keep the patients intact, safe, and alive, is significant. So we would have lost all the patients probably by even four to five months, or at least a large proportion. So that then, the long term here mitigates -- prevents us, really, from attributing absolute 100 percent certainty cause to VNS, because medicines will change. And I'll come back to that in a second.

One of the difficulties is if VNS works in one group, and the other group does not receive real VNS, there's a differential management with medications. One group will have medicines changed at a different rate or time or so on. We'll come back to that.

Another possibility that we thought of is simply go after electroconvulsive therapy versus VNS acute, in an acute trial modality perhaps. A couple, two, three, four weeks -- I'm sorry, four weeks to, say, eight to twelve weeks. The problem is ECT is a terrific acute treatment, but can't be given over the long run in most patients. And VNS is not an acute treatment and has to be given over a long run. So it just wouldn't make any sense. And secondly, even as I showed you and Dr. Rudolph showed you, the patients entering the VNS trial, 40 to 50 percent had already had ECT and had failed. Thirty-some percent, 38 percent in the current episode. So we'd have to change the patient population.

Another possibility we discussed at length, and really brought this around, was the idea of taking the patients who had received VNS who had benefited from the D01 trial or the D02 trial and simply randomizing them to a discontinuation. Just turn off the device. Two difficulties with that. One is, of course, there's risking of un-blinding. But more important than that, we would probably need an even larger sample pool than could be generated. The problem is we went to patients. We asked them, we surveyed the patients directly. I spoke to a number of patients, other investigators did. To a person, and you heard it also from a patient today, the patient said with this emotion you are not going to turn this device off. I do not want this device to turn off. So we would have to go after people with really minimal benefit who might have been more willing to have the device turned off, but that's not the population that would be appropriate for discontinuation trial. Next slide, please.

DR. ELLENBERG: If you don't mind, can I interrupt?

DR. RUSH: Sure. Yes, sir. Please go back.

DR. ELLENBERG: In the first bullet.

DR. RUSH: Yes.

DR. ELLENBERG: If I remember correctly, there were a significant number of meds changes in D02.

DR. RUSH: That's correct.

DR. ELLENBERG: So --

DR. RUSH: And a significant number in D04, which I think --

DR. ELLENBERG: Understood.

DR. RUSH: Take D04 as evidence that you couldn't do this with medications not changing.

DR. ELLENBERG: Well, that's what I want to follow up on.

DR. RUSH: Okay.

DR. ELLENBERG: So, the protocol as I recall, once the acute phase was finished allowed but discouraged medication changes in D02. And with that allowance you got, I think it was 60 percent medication changes. So in real life, that probably is going to be the way VNS will be given, with the allowance for medication changes.

So why then -- I understand your point based on the assumption that the cleanest way to do this is with no medication changes. But why couldn't a randomized trial be done where medication changes were discouraged but allowed, since effectively for the long-term results in D02 that's what happened? So why couldn't that trial be redone with the medication change discouraged but allowed?