1997 Neurological Devices Panel

[Anonymous]

1997 FDA CDHR Neurolocal Devices Panel

DR. COSTELLO: Good afternoon, Dr. Wilkinson and members of the panel. This afternoon, I will be discussing issues regarding the safety and effectiveness of the vagus nerve stimulation device......................One-third of the patients had some type of an increase in seizures, with 17 percent having greater than a 25 percent increase.................This slide shows each of the studies and the percent seizure increase. As you can see, in each of the studies, there were patients who had greater than a 100 percent increase. In the E05 study, the range went up to a 234 percent increase, while in the E04 study, it went even higher, to a 680 percent maximum range.

pg. 125
http://www.fda.gov/ohrms/dockets/AC/97/transcpt/3299t1.pdf


DR. PIANTADOSI: Yes; well, one of the things that's concerning me is that the endpoint being measured in all of these studies is, in some sense, a surrogate, counting the number of seizures. I realize that to the patient and to others, it is a very important endpoint, but it may not be as definitive as some other things that we could measure. And there are numerous examples in the methodologic literature about the weaknesses of accepting clinical trial data based on surrogate outcomes, and I would point to, as a recent and a very dramatic example, the cardiac arrhythmia suppression trial, in which the study was designed and the endpoint was selected on the basis of looking at arrhythmias and suppressing them with a drug. And the studies originally seemed to show that the drug was effective in suppressing arrhythmias. The problem was that it was so good in suppressing arrhythmias that it was killing people, and the mechanism was not understood until much later and wasn't even believed until the results of the randomized trial. So, I am very nervous when I see high mortality rates associated with a supposed benefit, even though we don't have a way biologically right now to connect the two. So, that is why I have harped on this this morning and why I am still very nervous with this high death rate. What's your sense of that? I mean, I'm struggling to get some reassurance that my concerns are not well-founded.

Pg. 135
http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3299t1.pdf



DR. PIANTADOSI: Could I just ask the FDA very directly--I'm not confused about what the company thinks, and I really am not interested in the nuances of how SUDEP is defined. Is the FDA satisfied that this device is not associated with an elevated risk of death, all-cause mortality, whatever you want?

DR. COSTELLO:............So, to answer your question, I don't believe it has been shown that the high death rate is directly related to the device. However, we only have 2,000 patient years of experience and a limited number of patients...............I cannot say that I believe that there is an increased risk right now, but I would not want to rule it out either. I think that would require a longer-term study.

Pg. 142
http://www.fda.gov/ohrms/dockets/AC/97/transcpt/3299t1.pdf

The VNS was approved 19 days after this panel met.

 

[Anonymous]

1997 FDA CDRH Neurological Devices Panel

DR. DUFFELL: Because it has come up twice. I just want to make sure--I don't know that I was perfectly clear. The output current, I understand your concern, both of you. You have to realize that it is a rate limiting phenomenon by the patient himself. I think any of the doctors here would tell you: since this device is going on and off every 5 minutes, if they can't tolerate it, they won't leave. You know, they only go to the level of perceptibility and comfortable tolerance. You would never have an instance where a patient went home and, all of a sudden, should have a reaction to an output current, because they will have seen it before they left the office.

Pg. 185
http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3299t1.pdf

 

[Anonymous]

1997 FDA CDRH Neurological Devices Panel

DR. CANADY: You mentioned in your presentation just now that in looking at the EEG results of humans that you didn't see any changes. Is there any electrophysiological data, either by telemetry or Holter monitoring of anything other than self-reported seizure frequency?

DR. NARITOKU: I think the question arises whether they are by visual analysis or by spectral analysis, and I think the person probably best to answer it is Dr. Salinsky,who has actually done the studies on EEG. May I refer it to him?

DR. SALINSKY: We performed a study during the E03 protocol looking at spectral analysis of EEG segments before the stimulator was turned on, during stimulation and then after stimulation, so, this was not a chronic experiment; it was strictly an acute experiment in patients using the device. We looked at, I believe, six patients. We did not see any significant changes in background EEG. Now, this was not ictal EEG; this was background EEG. There have been other reports, specifically from Dr. Uthman's group--I think he's here as well--and Dr. Hammond looking at EEG by visual inspection, and again, there do not appear to be any changes in the background EEG pattern. Nobody has yet investigated whether there are any specific changes in an ictal EEG pattern in humans. That would be, obviously, much more difficult to do.

Pg. 78
http://www.fda.gov/ohrms/dockets/AC/97/transcpt/3299t1.pdf


* Investigating whether there are any changes to an ictal EEG pattern during VNS stimulation would not be "difficult to do." As a matter of fact it would be very easy. Video-EEG is the way to do it. When the patient feels an aura they use the magnet to swipe the device and Wah-Lah - You have captured a seizure on EEG while the device is stimulating.

Dennis Fegan

 

[Anonymous]

1997 FDA CDRH Neurological Devices Panel

DR. SNEAD: I think that's a reasonable suggestion. I would like to just say a word of caution about including children at this date. First of all, I am not convinced that we have data to do that. Secondly, what we have heard about today are that the patients will tell you when the stimulus is too high, because they are uncomfortable, because of the voice change. Well, some children are not able to do that, and some children are severely neurologically handicapped; some children are too young, and you really need to be very careful about extrapolating these data into that kind of population.

DR. WILKINSON: Any other comment, then, about this question?

DR. SPYKER: I'm not sure I understood the suggestion. We already have it back in the has not been shown effective. That's on page 12, and I guess, well, so,the question stands: do we want to leave this in the indication section. I don't propose that we remove it from back in individualization of treatment?

DR. WILKINSON: It's already in that paragraph.

DR. SPYKER: Yes, sir. Thank you.

DR. WILKINSON: Yes. So, leaving it in this paragraph would emphasize the lack of data for the 12-year-old age cutoff, but not listing it as an absolute contraindication would still leave the clinician some leeway, so, perhaps leaving this in does make sense.

DR. DUFFELL: Could I make a comment on that?

DR. WILKINSON: One quick comment.

DR. DUFFELL: I agree with what you're saying, but what we also need to remember is that what the indications state also greatly influences what the payers will pay for. So, the panel needs to consider that as well. We will work with the FDA to constructively work out whatever the label should be, but I wouldn't want you to neglect that in your considerations as well.

DR. WILKINSON: And also, the future will come, and with the future may come data.

[Laughter.]


pg. 201
http://www.fda.gov/ohrms/dockets/AC/97/transcpt/3299t1.pdf



Dr. Wilkinson - Committee Chairman

Dr. Snead - Committee voting member

Dr. Spyker - FDA

Dr. Duffell - Cyberonics

 

[Anonymous]

1997 FDA CDRH Neurological Devices Panel

DR. REID: Thank you, Dr. Duffell, Chairman Wilkinson, distinguished members of the panel. I appreciate the opportunity to make this presentation to you today. I have no financial interest in the Cyberonics Corporation,but they did pay my way to come here to speak to you.

The procedure is performed for selected patients after routine presurgical evaluations. The NeuroCybernetic Prosthesis provides an additional tool for the neurosurgeon in his armamentarium against epilepsy. The entire patient system is implanted, with no transcutaneous leads, and so, patients can, therefore, participate in athletics and other activities unrestricted. The procedure has been done by neurosurgeons, vascular surgeons and other surgeons familiar with surgery within the carotid sheath. The NCP system implantation is fully reversible surgically. ..............

Hoarseness, persistent, not related to the stimulation, occurs in approximately 1 percent of the patients and should be followed with immediate laryngoscopy and removal of the lead if the vocal cord is noted to be paralyzed; otherwise, it usually recovers.

pg. 49
http://www.fda.gov/ohrms/dockets/AC/97/transcpt/3299t1.pdf

 

[Anonymous]

1997 FDA CDRH Neurological Devices Panel

Mr. Chairman, members of the panel, my name is Martin Salinsky. I'm with the epilepsy program at the Oregon Health Sciences University in Portland, Oregon. I am also a consultant to Cyberonics, Incorporated, and Cyberonics has paid my way to this conference.
............................................................. In study E03, 115 patients were implanted, but one withdrew prior to randomization due to an informed consent problem. There were 114 patients in the efficacy population. 112 patients actually completed the study. One patient withdrew at about 6 weeks of stimulation due to a device malfunction, and another patient withdrew after 8 weeks of stimulation after suffering a non-fatal myocardial infarction.

pg. 57
http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3299t1.pdf

 

[Anonymous]

1997 FDA CDRH Neurological Devices Panel

DR. DUFFELL: I mean, I can comment briefly before Marty makes his statement that, I mean, certainly the intent of the company to make sure that the individuals who implant and treat with the device are adequately trained, and one of the things that we are striving and working with the agency over the labelling is to make sure that the labelling, of course, very appropriately says what the device is and is not capable of doing so that the expectations will be right. We're not interested in seeing this thing prescribed like aspirin for the treatment of epilepsy. It would be counterproductive to our commercial success years from now to have that happen.

Pg 101
http://www.fda.gov/ohrms/dockets/AC/97/transcpt/3299t1.pdf
______________________________________________________________

Model Number 102
Event Date 11/01/2002
Event Type Injury Patient Outcome Life Threatening;
Manufacturer Narrative
Report is incomplete because attempt to obtain additional information has been unsuccessful to date.
Event Description
Patient has had an increase in seizures since their implant. The patient had been having 1 seizure every month or every other month and is now having 2-3 seizures a month.

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=448108

Event Date 01/01/2003
Event Type Injury Patient Outcome Life Threatening;
Event Description
Reporter indicated that the pt had experienced a total of 13 seizures the year prior and that pt had only experienced a total of 5 seizures 3 years before, prior to being implanted with vns therapy system.
Manufacturer Narrative
Report is incomplete due to the anonymous nature of the reported event. The pt did not give their name at the time of the initial report.

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=550791

Model Number 102
Event Date 10/01/2003
Event Type Injury Patient Outcome Life Threatening; Required Intervention
Event Description
Further follow-up revealed that the patient wants to have the device programmed to off and possibly explanted. Neurologist is considering programming the device to off.
Event Description
Reporter indicated that vns pt had experienced an increase in seizures since stimulation was initital. It was reported that pre-vns implant, the pt had one seizure per year. The pt has had approximately one seizure per week since initiation of vns therapy and that there had been no recent changes to their drug regimen. Further follow-up revealed that treating neurologist plans to increase vns settings and possibly decrease anti-epileptic medications. Neurologist indicated that the relationship between the vns therapy system and the reported event was unknown. The pt is still with increased seizures.
Event Description
Further follow-up revealed that the pt has been seizure free for approximately 4 months. Neurologist indicated that the pt has likey experienced greater benefits from vns therapy than the pt realizes. The cause of the reported increased seizures in unknown due to conflicting information from the pt and neurologist.

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=508838

Model Number 102
Event Date 03/01/2004
Event Type Injury Patient Outcome Life Threatening;
Event Description
Reporter indicated that pt has recently experienced an increase in seizures. It was reported that the pt experienced 1-2 seizures per year prior to vns implant and that pt recently experienced 3 seizures within one month. Treating neurologist indicated that the pt was doing fine and that the reported event was not related to the vns. The pt's seizures types had not changed. The pt's health condition is reportedly not worsening and there were no environmetal stimuli that may have contributed to the increase in seizure activity. Neurologist indicated that programming the pt's device to off resulted in no change to the pt's condition or symptoms.

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=522645

 

[Anonymous]

1997 FDA CDHR Neurolocal Devices Panel

DR. COSTELLO: Good afternoon, Dr. Wilkinson and members of the panel. This afternoon, I will be discussing issues regarding the safety and effectiveness of the vagus nerve stimulation device......................One-third of the patients had some type of an increase in seizures, with 17 percent having greater than a 25 percent increase.................This slide shows each of the studies and the percent seizure increase. As you can see, in each of the studies, there were patients who had greater than a 100 percent increase. In the E05 study, the range went up to a 234 percent increase, while in the E04 study, it went even higher, to a 680 percent maximum range.

pg. 125
http://www.fda.gov/ohrms/dockets/AC/97/transcpt/3299t1.pdf


DR. PIANTADOSI: Yes; well, one of the things that's concerning me is that the endpoint being measured in all of these studies is, in some sense, a surrogate, counting the number of seizures. I realize that to the patient and to others, it is a very important endpoint, but it may not be as definitive as some other things that we could measure. And there are numerous examples in the methodologic literature about the weaknesses of accepting clinical trial data based on surrogate outcomes, and I would point to, as a recent and a very dramatic example, the cardiac arrhythmia suppression trial, in which the study was designed and the endpoint was selected on the basis of looking at arrhythmias and suppressing them with a drug. And the studies originally seemed to show that the drug was effective in suppressing arrhythmias. The problem was that it was so good in suppressing arrhythmias that it was killing people, and the mechanism was not understood until much later and wasn't even believed until the results of the randomized trial. So, I am very nervous when I see high mortality rates associated with a supposed benefit, even though we don't have a way biologically right now to connect the two. So, that is why I have harped on this this morning and why I am still very nervous with this high death rate. What's your sense of that? I mean, I'm struggling to get some reassurance that my concerns are not well-founded.

Pg. 135
http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3299t1.pdf



DR. PIANTADOSI: Could I just ask the FDA very directly--I'm not confused about what the company thinks, and I really am not interested in the nuances of how SUDEP is defined. Is the FDA satisfied that this device is not associated with an elevated risk of death, all-cause mortality, whatever you want?

DR. COSTELLO:............So, to answer your question, I don't believe it has been shown that the high death rate is directly related to the device. However, we only have 2,000 patient years of experience and a limited number of patients...............I cannot say that I believe that there is an increased risk right now, but I would not want to rule it out either. I think that would require a longer-term study.

Pg. 142
http://www.fda.gov/ohrms/dockets/AC/97/transcpt/3299t1.pdf

The VNS was approved 19 days after this panel met.

Thank you for publishing the link to the FDA site. I was concerned by your excerpts so I went to the site and read the ENTIRE document. I suggest others read though ALL the information before drawing any conclusions.