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Meeting Transcript - ASK CHILDREN (Assess Specific Kinds of CHILDREN Challenges for Neurologic Devices) STUDY Workshop, September 13, 2010

FOOD AND DRUG ADMINISTRATION

ASK CHILDREN STUDY WORKSHOP

September 13, 2010, 9:00 a.m.

FDA White Oak Campus

10903 New Hampshire Avenue

Life Sciences Building 64

Silver Spring, Maryland 20993

OPENING COMMENTS BY CARLOS PENA, OFFICE OF THE CHIEF SCIENTISTS, OFFICE OF THE COMMISSIONER, FDA

DR. PENA: Okay, we'll to get started, here.

I'd like to welcome everybody to the ASK CHILDREN Study Workshop. I'd like to welcome the workshop participants, the public attendees, and the FDA staff.

The purpose of this workshop is that -- FDA has organized this meeting to solicit information from academic investigators and clinicians associated with the use, research, and development of pediatric neuroprostheses regarding approaches for enhancing the protection and the promotion of public health in children and adolescents with these products.

Before we move to opening remarks by Dr. Jeff Shuren, I'd like to review a couple of housekeeping items.

First, this is not an advisory panel meeting. We will not being asking the discussants to reach a consensus decision or take any kind of vote at the end of the day. We've called together this group together to speak from their own perspectives and, in some cases, the perspective of their organization.

This workshop is also not intended to promote any medical product as safe or effective, and the mention of specific devices, devices types, device areas, indications for use, is to illustrate a point or facilitate discussions.

Both FDA and the public believe in a transparent process for information-gathering. So, in general, the committee participants are aware of the need to identify any interest that may be affected by the topics they address, and their statement will be noted for the record. I understand presenters will do so during their presentations if they have something to disclose.

For other panelists who are not presenting, we ask that you identify such interests, if they exist, when you first engage in the discussion, and you only need to do it once during the course of the meeting.

At this time, I'd like to go around the table and have folks identify themselves and their affiliations. Perhaps we could start at the right-hand side.

DR. NUSSBAUM: I'm Debbie Nussbaum, from the Cochlear Implant Education Center.

DR. PENA: Just actually, can you repeat?

DR. NUSSBAUM: Can you hear me now? Sorry. I'll repeat that.

Debra Nussbaum, coordinator of the Cochlear Implant Education Center at the Laurent Clerc National Deaf Education Center at Gallaudet University.

DR. FRAZIER: I'm Charleene Frazier. I'm an information specialist with the National Spinal Cord Injury Association and United Spinal Association.

MS. RUSH: Good morning. I'm Lauri Rush, and I'm here as a parent of a child with a cochlear implant today, from the patient perspective.

DR. PENA: Yeah. And if you could just make sure to turn off your mics after you're done speaking.

DR. FITZPATRICK: Suzanne Fitzpatrick, FDA Office of the Commissioner, and I'm FDA's executive director for their institutional review board.

DR. COSTELLO: I'm Ann Costello. I'm a reviewer in the Neurological Devices branch. I've been with the agency for over 20 years. And I'm the head of the oversight committee for the study.

DR. EYDELMAN: Good Morning. I'm Malvina Eydelman. I'm director of the Division of Ophthalmic, Neurologic, and ENT Devices.

DR. SHUREN: Good morning. I'm Jeff Shuren. I'm the director of the Center for Devices and Radiological Health.

DR. KRAUTHAMER: Good morning. I'm Victor Krauthamer. I'm director of the Division of Physics.

DR. BOWSHER: I'm Kristen Bowsher, and I'm a reviewer in the Neurological Devices branch.

DR. PENA: Carlos Pena, senior science policy advisor in the Office of the Commissioner.

DR. SAMUELS-REID: Joy Samuels-Reid, medical officer, FDA.

DR. FRIEDMAN: Neil Friedman, pediatric neurologist, Cleveland Clinic.

DR. CHELONIS: John Chelonis. I'm with the Arkansas Children's Hospital, and I'm also with the National Center for Toxicological Research with the FDA.

DR. PEARL: Phillip Pearl, pediatric neurology, Children's National Medical Center, here in Washington.

DR. ROBINSON: I'm Shenandoah Robinson. I'm a pediatric neurosurgeon at Rainbow Babies, in Cleveland Ohio.

DR. PECKHAM: Morning. Hunter Peckham. I'm professor of biomedical engineering at Case Western Reserve University in Cleveland, and director of the Functional Electrical Stimulation Center there.

DR. TILTON: Ann Tilton. I'm a child neurologist with LSU Health Sciences Center and at Children's Hospital, New Orleans.

DR. MARKS: Warren Marks. Pediatric neurologist, director of rehab and movement disorders at Cook Children's Medical Center, in Fort Worth, Texas.

DR. WALTZMAN: Susan Waltzman, professor of otolaryngology and director, NYU Cochlear Implant Center, at New York University.

DR. PENA: Thank you.

So, just as a reminder, we have a one open public comment period scheduled for approximately 1:30 p.m. We have two presenters signed up. If there are other public attendees that'd like to sign up, please see Dr. Bowsher and I at during the break.

I would just remind panel members to turn on your microphones when you speak, so that the transcriber can pick all pick up all that you state, and turn it off when you're not speaking.

I also request all meeting attendees to turn their cell phones and BlackBerrys to silent mode.

Now that we've walked through some of the extensive, detailed housekeeping items, why don't we move to our first speaker and the welcome address from Dr. Jeff Shuren, director, Center for Devices and Radiological Health at FDA.

Jeff?

PRESENTATION BY JEFF SHUREN, DIRECTOR,

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH, FDA

DR. Shuren: Again, good morning. I'd like to welcome you to today's ASK workshop, and thank you for being here, for sharing your knowledge, your insight and ideas. It should be a very exciting workshop.

Today's event exemplifies CDRH's commitment to foster innovation and device development for all segments of the U.S. population, including children, especially those with chronic diseases or conditions that require or benefit from devices designed to meet their needs.

In addition, today and tomorrow we have a workshop on pediatric safety surveillance going on at the same time.

This workshop is the launch of a first in-Center effort to understand, from the children themselves, their experience with, preferences, their likes and dislikes about the neurologic devices they live with.

As we all know, children are not little adults. They undergo rapid growth and development, they think differently, they interact with their environment differently, they spend their days differently than do adults.

Consider the first year of life as an example. From birth to 1 year of age, the average infant will triple their birth weight. Imagine eating enough food to triple your weight. Some of us maybe dream of that on vacation, but probably couldn't sustain it. They evolve neurologically, from no head control at birth, supported sitting by 6 months, to crawling, then standing, cruising, or even single steps by 1 year of age. They communicate by crying, to language-specific babbling by 6 months, to pointing, understanding, or even using single words by 1 year.

Challenges continue on all fronts throughout childhood, with distinct spurts at puberty.

Children have a long shelf-life, if you will. Thus, understanding the long-term safety and efficacy of a device over its decades of use is critical knowledge to help CDRH more effectively oversee the device throughout its lifecycle, but also for manufacturers to make safer, more effective devices, that are better suited to meet the specific needs of children of different ages.

The ASK project will, for the first time, collect information from children themselves about their neuroprosthetic device: cochlear implants, deep-brain stimulators, hydrocephalus shunts, spinal cord stimulators, and vagus nerve stimulators.

So, thank you again for being here, and we look forward to your comments.

Because I have to leave before the first break, I'm actually going to sit behind all of you so I don't disturb you. But, I do look forward to everyone's comments.

Thank you.

[Applause.]

DR. PENA: Thank you, Dr. Shuren.

Our next speaker is Dr. Kristen Bowsher, expert reviewer in the Division of Ophthalmic, Neurological, and Ear, Nose, and Throat Devices at CDRH.

PRESENTATION BY KRISTEN BOWSHER,

DIVISION OF OPHTHALMIC, NEUROLOGICAL, AND EAR, NOSE, AND THROAT DEVICES, CENTER FOR DEVICES AND RADIOLOGICAL HEALTH, FDA

DR. BOWSHER: Hi. I'm Kristen Bowsher, and this morning I'm going to provide you an overview of the workshop's purpose and the discussion questions we'll speak about.

I will, first, briefly describe a few of the pediatric initiatives that led up to this workshop. Later this morning, Dr. Samuels-Reid will be speaking in more detail about these initiatives.

I have no conflicts or disclosures.

In 2002, the Medical Device User Fee and Modernization Act of 2002, better known as MDUFMA, was signed into law. Among other things, MDUFMA amended the Federal Food, Drug, and Cosmetic Act, or "the Act," by adding several new provisions intended to promote the development of safe and effective pediatric devices, and to protect pediatric populations during the course of clinical trials involving medical devices. As a result of MDUFMA, in 2004 a guidance document entitled "The Premarket Assessment of Pediatric Medical Devices" was development to help the agency achieve the intent of the pediatric provisions of MDUFMA.

Then, in 2007, as part of the Food and Drug Administration Amendments Act, or FDAAA 2007, the Pediatric Medical Device Safety and Improvement Act of 2007 was instituted. This Act included provisions for increasing the tracking of pediatric device approvals, modification to the Humanitarian Device Exemption Program, the establishment of nonprofit consortia, enhances -- and post-market surveillance and enhancements for to the Federal response for pediatric device needs.

In 2008, supplemental funding through FDAAA was received by the Center of Devices and Radiological Health for use in pediatric initiatives. The ASK CHILDREN Study received funding through this supplemental funding.

Dr. Pena is going to speak in more detail about this study later this morning, but I'm going to give you a brief overview, as this study is a prime motivator for this workshop today.

Basically, the ASK CHILDREN Study is an IRB-approved study to evaluate the regulatory barriers and associated factors needed to bring pediatric neuroprostheses to the market. The unique aspect of this study is that feedback is obtained directly from the children. The study is not looking at the safety and effective of effectiveness of the devices involved, as that has already been established through a premarket review process, but rather it is to look at things, such as human factors and usability, from the viewpoint of the children, directly, in a forward-looking effort to enhance research and development, promote device innovation, and aid in the regulatory review of these devices.

Currently, we have three sites enrolling patients: here -- the FDA -- the Cleveland Clinic, and Arkansas Children's Hospital. And, you will hear from those investigators later today.

The goal of the study is to enroll approximately 100 children, ages 7 to 15, with five different device types. So, we're shooting for 20 children for each device type. As Dr. Shuren stated, the device types include a deep-brain stimulator, cochlear implants, a spinal cord stimulator, a vagus nerve stimulator, and hydrocephalus shunts. The devices are all legally marketed for use in children, and went through a variety of marketing pathways, which Dr. Eydelman will describe in more detail later this morning.

In the next few slides, I'm going to quickly go over the approved or cleared indications in age ranges for each of the device types included in the ASK study. Again, I want to stress that the goal of this study is not to assess safety and effectiveness, since that has been established, but, rather, it is to look at firsthand experiences of the children using these devices, and to learn from these experiences with these marketed devices, and hopefully apply this knowledge to future development of neurological devices for children.

The first device that is included in the study is the Medtronic Activa Dystonia Therapy device. This is approved for unilateral/bilateral stimulation of the internal global globus pallidus or the subthalamic nucleus to aid in the management of chronic intractable primary dystonia, including generalized and/or segmental dystonia, hemi-dystonia, and cervical dystonia in patients 7 years of age or above.

This device was approved through our HDE program, which, again, Dr. Eydelman will go over in more detail, later this morning, but, in short, an HDE is a pathway for conditions that have an unmet need and have an incidence of less than 4,000 patients per year. The requirements for approval are different than the more stringent premarket approval process, in that a device must only demonstrate, in addition to safety, probable benefit outweighs the probably risk. I have included the Web page where you can find more information on the device approvals, at the bottom of each of the slides.

The next devices that we are looking at are cochlear implants. Currently, we have three manufacturers with approved devices, with an age range of greater than or equal to 12 months. Since there are many device models and various specific approved indications for use, I've not listed them all here, but I have included the Web page where you can find the approval specifications. They are all approved for some sort of hearing enhancement.

The next device that we're looking at is, again, HDE-approved. It's the NeuroControl Corporation VOCARE bladder system approved for ages greater than or equal to 14. The indications for use that was approved was to stimulate the sacral anterior root ganglia of the spinal cord for the treatment of patients who have clinically complete spinal cord lesions, through the ASIA classification, with intact parasympathetic innovation of the bladder and are skeletally mature and neurologically stable to provide urination on demand and to reduce post-void residual volumes of urine. Secondary intended use is to aid in bowel evacuation. And, again, I've included the Web site for more information.

The next device is a PMA-approved device: a Cyberonics NeuroCybernetic Prosthesis system, or the NCP system. It's approved for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents, over 12 years of age, with partial-onset seizures which are refectory to antiepileptic medications.

And the final device we're looking at is a 510-clear device. And our 510(k) program is basically our substantially equivalent or me-too process. Hydrocephalus shunts are cleared for the treatment of hydrocephalus to shunt cerebral spinal fluid from the ventricles, the peritoneal cavity, or other appropriate drainage sites, such as the heart's right atrium. Since the number of manufacturers with cleared devices is quite large, rather than list them all here, I've included, at the bottom of the slide, a reference to the FDA Web site in which you can look up these devices.

Back to why we are here today. The ASK workshop being held today stems from all these previous efforts I just discussed. The purpose, again, is to solicit information directly from academics, clinicians, public health advocates, pediatric users of these devices, and Federal Government representatives associated with the use, research, and development of pediatric neuroprostheses. The purpose is not to arrive at any sort of consensus, but, rather, to gather a variety of perspectives on neurological devices for children and adolescents. We hope that the information gained from today's discussion will help in defining guiding principles and protections that manufacturers can consider in designing new devices, and that will help shape the perspectives of how the FDA regulates these devices.

The main discussion questions that we want to talk about today are: What are the best approaches for enhancing the protection and promotion of the public health in children and adolescents with neuroprostheses? And what are the unique needs associated with currently marketed neuroprostheses for children and adults? So, keep these two questions in mind through your discussions today.

Discussion topics will include the unique considerations for children and adolescents, such as brain growth, unique surgical considerations, human factors, et cetera.

Another discussion topic will be evaluation time points, since long-term devices may need to be evaluated at intervals to ensure that children are meeting their developmental, psychological, and rehabilitative milestones. And we will also talk about some device-specific things that should be considered.

Oops, and I skipped a slide there. There you go.

So, the output of the this workshop will be a meeting transcript and a meeting summary, which we are going to post on the Web. I want to mention, the public docket for comment will remain open for quite a while. If you'd like to provide comment after the workshop, the Web page is on this slide. And as I stated previously, we hope that the information gained from today's discussion will help in defining the guiding principles and protections that manufacturers can consider and that the FDA can consider in regulating devices.

Thank you.

[Applause.]

DR. BOWSHER: And tax information.

DR. PENA: Thank you, Dr. Bowsher.

Are there any questions for Kristen?

Yes.

DR. PEARL: I was curious why intrathecal Baclofen pumps are not being covered. There must be some technical reason that I am not aware of, but I wanted to ask.

DR. PENA: Sure. I think, when the initial analysis was done, we tried to focus on those products that were in contact with CNS tissue of either the brain or the spinal cord. And for some of the spinal devices, we even went to the synaptic junction between the PNS and the CNS, but intrathecal Baclofens was not included in that initial analysis.

DR. PEARL: Okay.

DR. PENA: Our next speaker is Dr. Joy Samuels-Reid, from Division of Anesthesiology, General Hospital, Infectious Control and Dental Devices, at CDRH.

PRESENTATION BY JOY SAMUELS-REID,

DIVISION OF ANESTHESIOLOGY, GENERAL HOSPITAL, INFECTION CONTROL AND DENTAL DEVICES,

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH, FDA

DR. SAMUELS-REID: Good morning. Thanks for the opportunity to talk to you about pediatric medical devices and some of the initiatives that we have undertaken at the agency. We're particularly pleased to talk about this workshop and to give you some information about how it came about.

[Pause.]

DR. SAMUELS-REID: Thank you.

I have no disclosures, no conflicts to disclose.

And my talk will start off with pediatric initiatives. I'll give you a brief overview. I'll highlight a few of the initiatives, not all of them. I'll talk a little bit about the pediatric guidance and some of the unique considerations that we should keep in mind when discussing pediatric medical devices in children.

We've all heard of the barriers well, at least perceived some of them perceived, some real to pediatric device development in children. We've pretty much concluded that budgets sometimes can be cost-prohibitive. The array of devices, in terms of the different pediatric subpopulations, can make this a challenge. Regulatory issues sometimes can be a barrier. And there is reluctance, sometimes, to study children, both on the part of parents and investigators.

The IRB, Institutional Review Board, process can be a learning curve. And the ethical issues pertaining to children can be quite challenging, in terms of consent issues, assent issues. And issues of the randomized clinical trial data, sometimes thought to be the gold standard, can be challenging. We really need new, novel ways of accepting trial data for children. And, of course, we can't talk about children without talking about safety.

So, what are we doing? We're assessing unmet needs for children, with respect to pediatric medical devices. We convened a workshop, a couple of years ago, with NIH, FDA, and ARC. And, out of that, we understood some of the unmet needs, but we're still trying to make sure that we understand all of them, and this is an emerging field.

We're encouraging presubmission and postmarket discussions about trials involving children. We're assessing adverse events, looking at these adverse events to inform safety, tracking premarket and postmarket studies. And we are using those data to help inform pediatric guidance development. I'll talk a little bit more about the two existing pediatric guidance documents that have been alluded to earlier.

We're convening FDA workshops. You've heard about a couple of the workshops that are undergoing. And I'll talk more about those, as well. And promoting pediatric device innovation, through a number of our initiatives, to create research partnerships and outreach.

So, at the Center-level, we have a number of initiatives. The CDRH MedSun-KidNet program is a postmarket surveillance program. And I'll discuss that a little bit more in detail in a few slides.

The critical path initiative is a novel way of looking at new therapeutic approaches. And there's the CDRH-funded pediatric proposal, of which the ASK Study Workshop is one of them. We also are undertaking bioresearch monitoring for interventions related to pediatric trials, and starting early to look at those trials and to give feedback to investigators and sponsors.

One of -- our newest initiative is the Academic Center of Excellence Program, which is called the ACE Educational Outreach Program. And this is through the Commissioner's Fellows Office. We have outreach to existing and new clinical investigators.

So, what is MedSun? It's a medical product safety network. It's a 350-site outreach to different hospitals, large and small, community hospitals, academic teaching centers. And it's a realtime interactive network to recognize and report medical device problems and adverse events involving death or serious injury. And, through this network, we're able to have harmful events reported directly to us.

KidNet is a subnetwork of the MedSun network, and it helps to identify problems, particularly in the neonatal and pediatric ICU.

We have the FDA's Pediatric Consortia Grants Program, which is a multimillion dollar initiative that's administered through the Office of Orphan Products Development, and it supports the development of medical devices designed for children. It funds demonstration projects of pediatric devices. And, through the Office of Pediatric Therapeutics and CDRH, we are constantly looking at new ways to bring medical devices to market, one of which involves the Pediatric Advisory Committee, which is administered through the Office of Pediatric Therapeutics, for HDEs.

We've already talked about the ACE Program and the outreach to new and existing clinical investigators.

One of our CDRH-funded initiatives, as we mentioned, is the ASK CHILDREN Study. Well, we've had other workshops, and I think you heard Dr. Shuren mention a couple of them. The last one convened was the Neurological, Neurocognitive, and Quality of Life Assessments for Pediatric Patients. We also convened the Pediatric Trials Workshop, which looked at unmet needs, trial designs, and clinically meaningful safety and effectiveness data.

We are developing a congenital heart disease registry. And one of the other initiatives is to continue to develop different pediatric guidances through information gleaned from workshops such as this. The two existing pediatric guidances are: The Guidance for Industry and FDA Staff: Premarket Assessment of Pediatric Medical Devices, and The Pediatric Expertise for Advisory Panels: Guidance for Industry and FDA Staff. The latter involves ensuring that there is pediatric expertise on all panels involving pediatric data. And I'll talk a little bit more about the first one.

In terms of the Premarket Assessment of Pediatric Medical Devices, this guidance defines the pediatric subpopulations; it identifies general types of information needed to provide reasonable assurance of safety and effectiveness of devices intended for pediatric use. It defines the guiding principles and protections sponsors should consider for pediatric subjects in device clinical trials. And, in terms of what is the definition of "pediatric use," it's any use of a medical device in a pediatric population or any of the subpopulations in which there's a primary pediatric indication, or a more general indication, or considerable pediatric application is anticipated.

CDRH the guidance defines "children," as birth to 21 years, and we've defined it in -- and broken it down into four subpopulations, but we recognize there are other ways of defining these various populations. For purposes of the guidance, "newborn" subpopulation is considered birth to 28 days; "infants," 28 days to 2 years; a "child" group is 2 to 12 years; and "adolescents," 12 to 21 years. Within CDRH, we have transitional groups for the adolescents 18 to 21 years, where data that are no different from adults are considered in the usual path, but where there is difference where there are differences, for 18- to 21-year-olds, that are significantly different for adults, clinical data may be needed.

So, why do we need pediatric data? Adult data may be inadequate to predict pediatric risk and adverse events. They may be needed for verification of design modifications. And we're they are needed to develop an age-appropriate treatment regimen.

We've heard the mantra before, "Children are not little adults," but there are different pediatric subpopulations; different metrics, sizes; height, weight, surface area are all different, not only among the different subpopulations, but between adults and children. There's different anatomy and physiology; the pathophysiology may be different; different lab indices; different ranges for normal and abnormal; different adverse events; different risk; and therefore, different mitigation strategies needed.

Some of the unique considerations the guidance discloses include growth and development issues. You've heard the introduction given by Dr. Shuren on some of the developmental milestones, and those have to be kept in mind; the impact of device of the device on the child, and vice versa; the activity level, maturational level, influences of puberty -- all have to be considered. And, because of this, device-area development of devices is completely different than in adults. The levels of maturity, immaturity of various organ systems have to be considered. What are the hormonal influences, whether or not it's a disease state or the normal developmental milestones of puberty?

We can't talk about the pediatric population without talking about behavior and psychosocial factors. You'll hear a little bit more from our speakers about this area and some of the neurocognitive issues.

I'd like to turn your attention to human factors and children, and device design safety and user interface issues. The what is the optimal size of the device? This has to be considered, not -- in terms of the pediatric population generally, but also in terms of each of the different subpopulations. Is the device portable? How easy is it to use? Is the usability age-appropriate? What are the physical and developmental differences that would be needed for each of the various subpopulations? What is the impact of activity on the device? Is the child ambulatory or confined? And what sort of supervision is needed for proper use of the device?

So, some of the pediatric-specific issues include the following: For each targeted subpopulation, we should ask, Will the child outgrow the device? Will adjustments be necessary? Will this require a staged approach? Will further intervention or reoperation be needed? What are the sorts of protection and safeguards that we need to have in place for each subpopulation? Is there adequate education?

We know that pediatric patients are usually supervised by various people, depending on where they are. So, it's not just the user, but also the guardian, the parents, and, in some cases, teachers must understand how to use the device.

Are there age-appropriate tools? What are the kinds of support systems needed to adequately use the device? And in depending on the age of the child, are there audiovisual aids, for instance, that should be developed to better enable a child to interact with a device? Are there pediatric-specific emergency measures in place? Is there adequate pediatric expertise? And are the devices properly sized for each of the subpopulation?

So, that's sort of an overview of our guidance, some of our pediatric initiatives. And just to reemphasize our other FDA workshops, Dr. Shuren mentioned the other workshop that coincides with ours, convening now and tomorrow. We have a cardiovascular workshop on pediatric issues at the end of the month, in San Francisco. And we have another workshop, the Public Workshop on Cell and Gene Therapy: Clinical Trials in Pediatric Populations, convening on November 2nd of this year.

Thank you.

[Applause.]

DR. PENA: Thank you, Dr. Samuels-Reid.

Are there any questions for Joy?

[No response.]

DR. PENA: Okay.

Why don't we move to the next presenter.

Oh, I'm sorry. Dr. Marks?

DR. MARKS: Yes. Just one quick question. How did they arrive at adolescence from 12 to 21? That covers a huge developmental and physical maturity change. And I know that for when you're talking about, particularly, these implantable devices, developmentally there's there are huge issues. And, you know, adult centers will often take on what they define as adolescents, and they, typically, do not consider 12-year-olds something that they would take on, but they would consider a 15- or 16-year-old because of a lot of issues.

DR. SAMUELS-REID: I think we generally agree with that. We don't these boundaries are not hard and fast; and, because devices are so different, different norms may apply for different devices. The 12- to 21-year-old was just sort of a general category, but we do recognize there are other ways of defining them, depending on what you're looking at. We agree that the different differences in developmental milestones, different level of reaching puberty, will all apply. So, it really depends.

I think, for ease of the guidance, we came to that sort of broad category, but we do we are flexible, in terms of how we break it down.

DR. PENA: Okay. Thank you.

Our next speaker is Dr. Malvina Eydelman, director of the Division of Ophthalmic, Neurological, and Ear, Nose, and Throat Devices at CDRH.

PRESENTATION BY MALVINA EYDELMAN, DIRECTOR,

DIVISION OF OPHTHALMIC, NEUROLOGICAL, AND EAR, NOSE, AND THROAT DEVICES, CENTER FOR DEVICES AND RADIOLOGICAL HEALTH, FDA

DR. EYDELMAN: Well, good morning, and thank you for coming.

As Dr. Bowsher stated, today's workshop is to solicit your feedback on use, research, and development of pediatric neuroprostheses. One of the main questions for the workshop today is, What are the best approaches for enhancing the protection and promotion of the public health in children and adolescents with these devices?

In order for us to be able to have a fruitful discussion, I thought it would be helpful to give a brief overview of the medical device regulations and some of the opportunities and challenges in this arena.

What is a device? Device is an apparatus that diagnoses, cures, mitigates, treats, or prevents a disease or condition, and does that in a nonmetabolic manner, and does not achieve its intended use through chemical action.

Center for Device and Radiological Health, or CDRH, as you keep hearing this morning, is in charge of getting safe and effective devices to market as quickly as possible, while ensuring that the devices and radiological products currently on the market remain safe and effective. Hence today's workshop. We're discussing the products which are currently on the market, and we want to know what else can be done.

All of the devices that are regulated by the FDA are regulated via risk-based paradigm; i.e., the law gives us the flexibility to calibrate our regulatory approach to the level of the potential risk posed by the new products. So, as you can see, the hydrocephalus shunts are a 510(k); DBS, for dystonia, it was an HDE; and a vagus nerve stimulator arrived to market via PMA route.

The medical devices are classified into three classes. And, additionally, we have two unique classifications, which are HD and the de novo process. Class I is for simplest design, for the lowest-risk devices, and most are exempt from premarket submission. Class II is for more complex or high risk, and most of these come to market via 510(k) or premarket notification. Class III is reserved for the highest risk, and the premarket application is needed.

And here are some of the neurological device examples, just to give you an idea. So, for Class I, it would be manual surgical instruments, tuning forks. And DBS and vagus nerve stimulators would be all the way in Class III.

Once again, for Class I devices -- those are lowest-risk devices -- only general controls are needed. And most Class I devices are exempted from a premarket notification, or a 510(k).

For Class II, general controls plus special controls are needed, and that's because general controls are insufficient to provide reasonable assurance of its safety and effectiveness. And there are various things that can be special controls, anything from the standards guidance, patient registries; and most of these Class II devices do require a 510(k) or premarket notification.

This mic is acting up.

Class III devices are the most complex or the most risky devices, are general controls plus a PMA. And these are typically reserved for devices that support or sustain human life, have substantial importance in preventing health impairment, or potential unreasonable risk of illness or injury. And you have some of the pictures to give you an idea, once again, of what kind of devices we're talking about.

Most of the devices that do require pre- some kind of a submission, come to the market via 510(k) or a PMA route. And again, PMA is for class III, and 510(k) for Class II, and some, very few, nonexempt Class I's.

510(k) is a marketing clearance application and it allows FDA to determine substantial equivalence to a predicate device. Substantial equivalence is: if in comparison to a legally marketed device, the device is found to have the same intended use and the same technological characteristics as the predicate device or if it has the same intended use and has different technological characteristics and the information in the 510(k) does not raise new questions of safety and effectiveness and it demonstrates it as safe and effective as a predicate.

PMA, on the other hand, is for Class III devices now that I've said it ten times, I'm sure you can remember and this application needs to contain sufficient valid scientific evidence to provide reasonable assurance that the device is safe and effective for its intended use. And when we evaluate a device for safety-and-effectiveness determination, the considerations are given to intended populations, conditions of use for the device, the probable benefit to health versus probably injury or illness from use, reliability of the device. And our decisions are based on valid scientific evidence only.

The distinction, once again, between the two processes are summarized here. 510(k) is a clearance, PMA is an approval. Most 510(k)s are for Class II; PMAs, for Class III. For 510(k), the application only has to demonstrate that the device is substantially equivalent to a predicate, while, for PMA, the device needs to be shown to be reasonably safe and effective for its intended use.

I think that's enough.

HDE, or humanitarian device exemption. Kristen mentioned this earlier this morning. And, this comes to us from the section 520(m) of the FDNC, which basically reads that it is intended to encourage the discovery and use of the devices intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect fewer than 4,000 individuals in the U.S. Essentially, the intent of this provision is to provide incentives for development of devices intended to treat or diagnose small patient populations, where otherwise a device manufacturer's R&D costs could exceed the market returns.

And, once again, the HDE kind of devices are usually not otherwise available. And no comparable devices need to be available through a 510(k) or PMA. The device, under the HDE, should not pose unreasonable risk of illness, and probable benefit should outweigh the risks.

HDE is an approval application. It authorizes marketing of a humanitarian-use device. This is a very common point of confusion; hence I'm dwelling on it. Unlike other avenues, though, HDE requires IRB approval before the device is used. And labeling must clearly identify a device as a HUD.

HDE versus PMA: Both are marketing approvals, both subject to postmarket MDRs, however the approval thresholds differ. For PMA, we look for safety and effectiveness; for HDE, just safety and probable benefit.

So, now that I went over many different ways to bring the pediatric devices to market, I want to accentuate the fact that FDA's job is not over once the device is approved. We continue to monitor device performance through many different avenues: post-approval studies, in some cases; mandatory adverse-event reports; annual reports from manufacturers; we monitor the scientific literature; we attend budget dependent the scientific and clinical meetings; and we hold workshops, like we're doing today.

Information learned in postmarket settings, such as today's workshop, may be used in a number of ways. Device modifications, labeling changes, modifications in how we review the next generations of these type of products, and directed physician and patient outreach, as in information that we provide via Web sites, publications, and public health notifications. Hence, the workshop and its output today hopefully will support our mission to support the total product lifecycle of these devices.

Thank you.

[Applause.]

DR. BOWSHER: Does anybody have any questions for Dr. Eydelman?

[No response.]

DR. BOWSHER: Okay. Then we'll I'll introduce the next speaker, who's Dr. Carlos Pena, the senior science policy advisor in the Office of the Commissioner.

PRESENTATION BY CARLOS PENA, OFFICE OF THE CHIEF SCIENTIST, OFFICE OF THE COMMISSIONER, FDA

DR. PENA: So, good morning, workshop panel members, public attendees, FDA staff. I'm scheduled to present to you a FDA-sponsored study called the ASK CHILDREN Study.

And I have no disclosures or conflicts of to report.

The ASK CHILDREN Study is an abbreviation for "Assessing Specific Kinds" of children challenges for neurologic devices and involves children implanted with a medical device to treat a neurologic disorder or condition.

And I'm sure most of you have heard the anecdotal story of a truck getting stuck underneath a bridge during a traffic jam, and that the firefighters couldn't come, they couldn't get the truck out. It was wedged underneath that overpass. Police couldn't get it out. And there was a little girl that said, "Why don't you just let the air out of the tires?" And when they did that, the truck was able to be detached from the underneath the overpass. That's the type of insight we're looking for from the patients that we're working with in the ASK CHILDREN Study, getting the patient perspective and considerations that we would normally otherwise not hear from when looking at these products under review.

So, with that intro, the origin of the study originates from FDA staff having an interest in pediatric medical devices. It also originates from performing a preliminary assessment of pediatric medical devices with neurologic indications for use. And it's also a desire to obtain additional input from the patient perspective.

There are three main objectives to the study. It's to collect patient self-reported data in children with neurologic devices to identify human factors, safety, usability, and other events important for future products, including the identification of early postmarket challenges. Second objective is to plan, organize, and execute a public meeting of patients and subject-matter experts, like we have around the table, to hear and discuss pediatric considerations that can be folded in and understood in the context of the study. And then the third is to develop recommendations involving the very patients we are trying to help.

The trial design is pretty straightforward, in that it does not involve a medical intervention and, rather, it looks at patients who already have a medical device for an improved indication for use. It's a prospective, nonrandomized, patient self-report study that has multiple sites, and it targets 100 children and adolescents, both male and female, ages 7 to 15 years of age. And they must be implanted with the medical device to treat a neurologic disorder condition under the approved label for that product.

This study is like what you would have with any other study, it's been IRB received initial IRB review in 2009, in the study when the study was first proposed. And it also receives annual IRB reviews each year. In addition, if there are amendments to the study, if there are protocol changes or updates to the study materials, each of these changes must be reported to the IRB, just like you would have for any other study. And our team has learned quite a lot about IRB submissions, as we have seen what we thought we were experienced with, but doing it yourselves is creates a whole new world for us.

We have also taken the study very seriously, in that we've organized an oversight committee, which -- it was recently organized with an increasing enrollment of patients. Since we are not performing a medical intervention, and all the patients are using products with approved indications, the desire was to still have an independent oversight committee to evaluate the progress of the study at intermediate time points as they developed. The purpose of the oversight committee is to protect the patients, review the study data, and propose trial design changes, as needed.

So, one comment we heard from the IRB was that, "Well, you know, after the first 20 patients, it might be helpful to analyze the data that you've collected, to see how the protocol can be updated to better serve the to better help the study outcome." And we're hoping that the oversight committee takes an active role in independently performing that evaluation, in parallel to the FDA team the research team that's involved with the study.

I'm pleased to identify Dr. Ann Costello, who will be leading the oversight committee and working with the clinical team over the course of this study.

The eligibility criteria includes the following: for inclusion criteria, ages 7 to 15 years of age, implanted with a medical device to treat a neurologic disorder less than 12 months, implanted or approved or cleared for pediatric use, and a sign informed consent document. In addition, the exclusion criteria includes: participation in any other clinical investigation -- since this does not involve an active medical intervention, we consider those patients that are undergoing those procedures, they should take the that those studies should take priority; and children with significant cognitive impairments. Being that this is a pilot study, we're hoping to gain as much information from patients who can communicate their perspectives to us. And if this pilot study provides valuable, useful information at the end of the study, we would consider its application to other device areas or other patient populations where there may be more cognitive impairment associated with that disease or disorder or condition.

So, what are the types of devices we are interested in? And they include the following and Dr. Bowsher's gone over this previously a deep brain stimulator, a spinal cord stimulator, the CFS shunts, the vagus nerve stimulator, and the cochlear implants. The devices of interest were chosen while performing a preliminary assessment of pediatric medical devices with neurological indications for use and in contact with either the brain or spinal cord systems, or work later published in neurology. I would also like to note that this device area is an emerging science area -- specifically, neurologic medical devices -- as we continue to learn about the nervous system and the application of medicine to treat these disorders or conditions.

In preparing to get the study started, we developed a number of case report forms and used a number of questionnaires during the study. One of the case report forms looks at demographics, the age, the condition, age at implant. A second case report form looks at device-specific information -- the device type, the indications for use, the number of devices that are implanted, the device history. A third looks at child/adolescent information, this is for: What does the patient like about the products? -- dislikes, improvements to the device. The fourth is the quality-of-life information, its use at home, at school, and additional comments provided by the patient. And the fifth is the emergency contact information, should it be needed during the course of the study.

There are also three questionnaires. Two questionnaires, they use throughout all the patients: the ASK questionnaire and the child health questionnaire. Both are standardized assessment tools. And then, we also have a third questionnaire, the abbreviated profile of hearing aid benefit for the cochlear impatient cochlear implant patients subpopulation.

Okay. So, what is the patient experience like during the course of the study? The study is quite similar to other studies. There's a recruitment phase, where we talk with potential patients and their families about joining the study. And for those patients that are interested in the study, then we perform informed consent. There are two visits during the course of study, 6 months apart, and with a check-in in between both visits one and two. And then at the end of the visit two, there'll be a pooling of the patient data collected from the study, by the team that's involved.

The progress to date includes enrollment of patients in three of five neurologic device areas of interest, with the in following with the following enrollment numbers, for a total of 18 patients, to date. We have three patients with the deep-brain stimulators, zero patients with VNS, zero patients with the spinal cord stim, two patients with shunts, and 13 patients with cochlear implants. So, we're looking to not only increase the enrollment of those device areas that we don't have any patients for, but we're also, too, interested in meeting the enrollment target of 20 patients per device area, approximately 100 patients with a we we've identified a percentage of patients that may drop out, but we're targeting 20 patients per group.

So, to date, we have received data on some device considerations and patient experience when using with using their medical device. We've also received at-home and at-school comments, so far, with some of the first patients that have been enrolled in the study. Some of these comments have been their device use with families and amongst friends.

For example, a patient expressed the consideration of using their product with a baseball helmet. So, this is -- you know, from our perspective, we might be more interested in, maybe, the device use for that condition. But, you know, from the patient's perspective, it's very much important that they assimilate into life with their friends, with their peers, and so they made that comment. I think, when you look more closely at that comment, you kind of begin to identify the relationship between the device and their quality of life, and how they come together.

Another comment received was, when using one of the products, there was an error signal with the device when it was used incorrectly. And so, although the signal is needed for the correct device usage by the child, to the child it's important to be sensitive to how that signal is perceived by the child or adolescent, and not just indicating that it's -- you know, was wrongly used. It's, sort of, being mindful of what would be encouraging to that child to using that product effectively and safely.

We've received some additional comments from patients about ways to improve their product, as well.

And, as I mentioned, we plan to perform a 20-patient analysis for those patients who have completed both visits one and two. We have some patients who have completed both visits, and we are waiting to complete and go up to 20 patients before we do a that independent assessment, both by the oversight committee as well as the research team.

So, who are the stakeholders for this project? Well, first are the patients. I think it allows them to become active in a therapy that they're being treated for. It the other stakeholders are FDA staff, the public, clinicians and researchers, industry, and there's also public and congressional interests.

The short-term deliverables include the following: conducting a novel clinical research study to identify scientific and medical uses associated with pediatric use of these devices; obtaining information on human factors, safety, usability, adverse events, and possible postmarket issues immediately following implantation of high-risk devices, relevant to current and future neurologic applications; and then developing recommendations involving the very patients we're trying to help.

The long-term possibilities is that this study could serve as a prototype or a template for other medical device areas or topics of interest. It'll enhance the transparency with the outside stakeholders, Congress, and the public by taking a thoughtful and purposeful approach to addressing unmet pediatric needs by the agency. And it involves the very patients, again, who we're trying to help.

I'd like to just acknowledge some of the patients that have already been enrolled in the study to date.

And so, the next steps are we hope to continue to enroll, especially in the areas of in the device areas that we currently have no patients, but we're hoping to enroll those additional product areas. We've also have our study on the clinicaltrials.gov Web site. So, we're hoping to that then creates a little bit more awareness, at least here in the locally, in the D.C. area. But, we also have two additional sites: Arkansas Children's Hospital and the Cleveland Clinic, that are actively enrolling patients. And they've done I cannot say an outstanding job in helping us recruit patients.

Thank you.

[Applause.]

DR. BOWSHER: Do we have any questions?

Dr. Pearl?

DR. PEARL: When did enrollment begin? And what are the methods of enrollment? I mean, can we refer our VNS Clinic population to you, or does that represent some kind of bias and the patients have to find you on their own, that sort of thing?

DR. PENA: Yeah, I enrollment began in early spring of summer of 2009, and that was just at the first site, here in D.C. We had sort of a rolling enrollment phase while we brought on these other two sites to help with enrollments, since enrollment was a little bit slow.

I think part of the problem enrolling patients here in the D.C. area is that, if you look at the FDA's site, the patients are really not coming for another type of for something else of value to them, for a doctor's visit. Whereas, at the other two sites that we've been able to actively engage, there's an actual clinic there, where there's another purpose why they're making the extra trip. I think we have some incentives. We have a -- you know, a gift cards and T-shirts for their enrollment. But, I think, you know, it's been a little bit of a phasing of trying to increase in recruitment.

Regarding your second question, referrals, I think we would welcome any kind of information that clinicians and physicians might circulate to their staff, or to others that they see fit, to help enrollment here.

Yes, Dodie.

DR. ROBINSON: I was just wondering if you've approached any of the family advocacy groups, like Spinal Bifida Association or Epilepsy Foundation, because they obviously have a interest in collecting the information, as well, and they may help you get some referrals.

I was just thinking about my patients in my practice. And maybe 10 percent of them, of the vagal nerve stimulators and the shunt kids, would be able to participate in this.

DR. PENA: Sure. No, that's a

DR. ROBINSON: So, it's a very limited group that you're looking at.

DR. PENA: Right. No, that's actually a great question, because, at the beginning of the study, we worked with advocacy organizations in developing the protocol. And one of the first comments that they made was, "You know, you're looking at enrollment of just patients in the D.C. area." They said, "You might get a jaded perspective here, in this region." So, that -- that's why we went to the other two sites.

But, the advocacy groups were involved. I don't think we touched all the advocacy organizations that were out there. But, definitely following up, as you indicate, to try and increase their awareness, I think, would help our enrollment numbers.

DR. WALTZMAN: I have a question about the eligibility criteria

DR. PENA: Sure.

DR. WALTZMAN: for inclusion. Do they have to have the neurologic disorder for less than 12 months, or the device for less

DR. PENA: That was less the device of implant at less than 12 months. So, it's not the disorder, but they've had to have received the device within a 12-month period.

DR. WALTZMAN: Well, speaking to a cochlear implant, that really presents another set of issues for you

DR. PENA: Sure.

DR. WALTZMAN: because if a child is deaf and deaf -- congenitally deaf -- and gets a device, let's say, at the age of 14, that presents a whole other set of issues which affect their responses to the device.

DR. PENA: Right.

DR. WALTZMAN: Whereas, let's say the child is 15, has been deaf for only a year, and received it immediately; that's a different set of issues. So, I think that it's I don't know about the other devices, but, for a cochlear implant, how somebody responds, be it -- they a child or an adult -- is greatly affected by when they get it, what their status is, what their training is, and so on. So

DR. PENA: No, those are all excellent points. I would also encourage other there are other panel members here, part of the pediatric action team that we have for this study -- Doctors John Chelonis, Neil Friedman, Joy Samuels-Reid, and Victor Krauthamer, who are also part of this study -- in case they want to respond to different questions.

DR. KRAUTHAMER: I just wanted to add that we do capture those things, the length of the disease, length of the deafness, whether it's congenital or not. Those are all captured. So, we have that information, and this is an early study, more hypothesis-generating than pivotal in any way.

DR. PENA: Neil?

DR. FRIEDMAN: Carlos, if I can just make two comments about what's been mentioned. The one is that part of the protocol was amended to also allow for telephone contact of patients. Because one of the difficulties was trying to get patients in for the specific study, if they didn't have something else to do at the same time; and so, for patients, perhaps, at other centers that would be appropriate for the study, that's one possibility.

And then, the second is: the age restriction is a little bit of a concern, not just with the cochlear implant. If you look at VP shunts, they're generally put in at a very young age. And, as Dodie said, I mean, when you're starting to look at this age for placements of shunts, it's very hard. But, part of the protocol -- and correct me if I'm wrong here -- is, if there's any significant change to the device through this age range -- so if you're having a revision of a shunt, even if it's not the primary implantation of the shunt, or some significant revision to, say, an implant -- that those patients are also eligible.

DR. PENA: Dr. Marks?

DR. MARKS: Yeah, just a couple of comments. One is, when you're looking at some of the devices, particularly the DBS devices, a timeframe of 12 months may not be very effective. It can take a year before you see benefits from the surgery that you've undergone. And since there is no way to prescreen or pretest people, you may be getting incomplete data, in terms of positive benefit on their lives.

The other comment is that you have a limited number of centers, right now, participating in the studies. And not all of the centers do all of the devices. So, it with very little word about the study, I'm sure that's part of what's slowed recruitment. And then, asking people to travel significant distances to participate, I would think would make it a little bit more difficult.

So, I would I think that expanding your number of centers, and potentially expanding the duration with which the device has been implanted, would be very helpful.

DR. PENA: Thank you.

Yup.

DR. FRAZIER: Just to comment, again, along the line of expanding the centers. Certainly for the spinal cord stimulator, we know that there are three spinal cord injury dedicated units at the Shriner's Hospitals. So, that's a thought.

DR. CHELONIS: Well, one thing, to get at the question about getting to these sites and things like that. We just recently revised the protocol to actually have people do these things from home. So, at least as far as Arkansas, that's always a big problem, because it's a very rural area around there, and you've got people coming in from, you know, Tennessee and Missouri and things like that. So, we just sent the revisions in to the IRB, and we got them approved. And now we're getting site approval to have people so they don't have to come in twice. So, that should help with some of those comments you mentioned.

DR. BOWSHER: If there's no more questions, then I guess it's time for a 15-minute break. It's now 10 after. So, let's try and be back by 25 after.

Thank you.

[Recess.]

DR. PENA: And so, as we get started for the next speaker, I'd just reiterate the two questions that Dr. Bowsher had shown at the beginning of the presentation at the beginning of the workshop -- including, What are the best approaches for enhancing the protection and promotion of public health in children and adolescents with neuroprostheses? And what are the unique needs associated with currently marketed neuroprostheses for children and adolescents? I'd just ask the panel members to continue to turn those questions over, especially as we hear now from the clinical perspectives in the morning session and we move to the open panel discussion, when we've discussed those two questions further.

So, without further delay, we the next speaker is Dr. Shenandoah Robinson, Rainbow Babies Children's Hospital, University Hospitals, in Cleveland. She'll be giving a talk on devices for neurologic disorders in children and infants.

Dodie?

PRESENTATION BY SHENANDOAH ROBINSON, RAINBOW BABIES AND CHILDREN'S HOSPITAL, UNIVERSITY HOSPITALS

DR. ROBINSON: Good morning. So, I'm Dodie Robinson, and I'm a pediatric neurosurgeon. I happen to be the pediatric representative to our Drugs and Devices Committee for our National Neurosurgery Organization, and I devote a good part of my clinical practice to using these devices in kids, and treating these kids, lifelong.

I have no conflicts of interest related to this. And I have no financial incentive for using more or less devices. I will discuss off-label use.

So, we've heard, already, that children are not just little adults. And I think everyone in the room is well aware of that. But, I would also like to stress that I don't think that there is one cookie-cutter approach to the different devices. So, I think, as we look at these devices for our populations, we need to keep in mind that the different populations and different devices may need different types of IRB approvals and regulations.

So, I'm going to talk about hydrocephalus, primarily because that is, by far, the most common problem we deal with, but also touch on movement disorders and epilepsy. I'm not going to focus so much on the neuromuscular disorders; those are kids that have scoliosis and may need spine instrumentation, or the kids that need spinal cord stimulation. Those are actually very few children. With cerebral vascular disorders, our colleagues are using a lot a huge array of new toys, and those need to be available for kids, as needed. But, again, it's a very small number. The neurosensory disorders are primarily hearing and vision loss, and we do have the cochlear implants available now. Hopefully, visual implants will be coming on the horizon in the next 5 to 10 years, and we'll have to deal with some of those issues. And the deformational plagiocephaly I'll just touch on briefly. There's a helmet that's a Class II device.

So, these images are from a woman that's now 45 years old, and she has spinal bifida and shunt-dependent hydrocephalus. And she was actually one of the first patients to receive a shunt as an infant. So, these patients very much appreciate what the shunts do, because they know that the children born the decade before, all died. So, they know what it means to have a shunt. It's a little different than our children now, who grow up with shunts and only remember them in terms of their when they malfunction.

You can see, from all of these metal connectors near the neck, those illustrate some of the revisions she's had. She's had about 20 revisions over her lifetime.

So, general things we have to keep in mind, and with regard to the two questions that Carlos just mentioned, is that the neurologic disorders are lifelong challenges. So, there are a few kids that have epilepsy or other abnormalities that may resolve within childhood, but we're not really talking about those kids today. That's a small fraction of the kids, and these devices really don't apply to them.

And then, we have to keep in mind that our most of our patients who need these devices are multiply-affected. One of the rare exceptions is probably the kids with primary dystonia, where they have a genetic disorder, and all they have is the dystonia. But, if you look at our kids that have, say, a shunt for hydrocephalus when they were born preterm, and they're now 10 years old, about 10 percent will have severe spasticity, and some of those will benefit from or most of those will benefit from a surgical procedure, such as an intrathecal Baclofen pump; and about a quarter will have some form of autism; another quarter will have significant behavioral disorders that really interfere with their ability to learn and interact; and then a depending on how you define it, a third to a half will have epilepsy; and the biggest problem is that about half of them will have an IQ in the neighborhood of 70. So, that makes it very difficult when you're thinking about, "Well, if there is an option for secondary dystonia that they could either have an intrathecal Baclofen pump or they could have a deep brain stimulator" -- these kids aren't going to be able to consent for that procedure; and how we go through trials and everything with that makes it much more challenging.

Some of the disorders are life-threatening. I would argue that all of them impact their life dramatically. Kids do die from seizures. Kids have significant disabilities from spasticity and dystonia, and some of those are life-limiting. And hydrocephalus, of course, is often a life-threatening problem.

In addition to protecting the patients, I think we have to keep in mind that there are financial implications for these devices, not only with industry, but also in academics. So, we may not have consulting fees or things like that, but if your sensor is actively promoting, say, vagal nerve stimulators, and not DBS or something like that, that can make a difference to how these devices are presented to the children.

So, for shunts, there's hydrocephalus is an inadequate absorption for cerebral spinal fluid. And spinal fluid is the fluid that cushions the brain and the spinal cord. And so, basically, a shunt is a tube to take that extra fluid from the brain to another cavity -- usually now we use the peritoneum cavity in the abdomen -- and they require a valve.

So, this is just a simple example of what shunts can do. On the left side is a CT scan before the shunt, and the cerebral spinal fluid is black, and the brain is the gray ribbon around the outside, just inside the white skull. And you can see, after the shunt, that the brain expands. So, this is the ideal is that we would put this shunt in, and it would last the lifetime, and we would never have to revise it. The catheter that goes into the brain requires revision or it's the most common reason for revision; it accounts for about 70 percent of our revisions. And our revisions require surgery. So, there is no medical therapy. This is surgery only.

We have numerous types of valves. This picture is actually a gentleman, John Holter, who's an engineer; and his son had spinal bifida, and he developed one of the first valves in his garage. And that valve was used in clinical practice for about 30 years.

There's been numerous types of valves. And I think this really illustrates -- one of the problems we have is that these valves will be tested at different centers. And, in single-center trials, they would should significant improvement in the revision rate, and then, when we put them in multicenter trials, it doesn't hold up. And it's not that the surgeons or the team was particularly biased, but I think that there's difference in differences in populations, there's other differences in practice with shunts that make a difference in how the trails are done. So, all of our shunt trials need to be multicenter.

And then we put in tubing. When shunts first came out, they didn't put in enough tubing for a child to grow to adult size. Now we commonly do. And lengthening operations are not very common. So, there is an issue that we need to have shunts that can last a lifetime. The tubing often crumbles, usually somewhere around 20 years out. And this can be a significant issue. I've had several patients that have been 25 years between revisions, which is tremendous, except, when the revision happened, they actually weren't around the same family members that knew they needed to get in, and they actually got fairly sick before they got brought in.

The shunts malfunction. They malfunction quite a bit. It's we do several revisions a week, and that's very common for pediatric neurosurgeons. And it always requires surgery; and with that surgery, every time, you have the risk of infection, you have the risk of anesthesia and other complications.

The infection rates have been a significant problem. There was a national survey study done, in 2009, that showed that the infection rate for new shunts was 11 percent, which seems kind of high, but that was a survey from Cody and included all comers. In most centers, dedicated children's hospitals, where you have dedicated pediatric neurosurgeons, it runs much lower. And good rates are considered 3 to 5 percent.

We actually have an initiative in Ohio, with all the children's hospitals, where they're imposing a certain "bundle," which I'm not sure it's the bundle that's making the difference or it's the fact that our we have public reporting of our infections. And I think that draws people's attention to infection reduction. And they're down now to 3 percent across the State. So, I think those efforts can help. Shunt infections are a significant problem for you know, they require surgeries, a long hospital stay, they're expensive, but they also are a cause of cognitive decline, if you actually have a significant infection of the CSF in a meningitis-type picture.

So, we have done clinical trials for shunts. And these it's one of the few areas in pediatric neurosurgery where we've actually had good quality clinical trials. We know what the outcomes are; we know what the subpopulations are. And there is you can't really hide the fact that a kid's having difficulty with their shunt and that they require revision, in most cases. And so, it's fairly easy to define the parameters. And there's a high malfunction rate, so there's a lot of turnover. This is very different than when you're trying to look at outcomes for some of our other devices where it's a much more long-term process, in terms of failure.

The only other option, surgically, for shunts is the endoscopic third ventriculostomy, and you need to have a specific anatomy for that. That basically, the endoscopic third ventriculostomy is poking a hole in the floor of the third ventricle to kind of bypass the obstruction. And only a few patients are anatomically suited to have this procedure, and there's limited efficacy in infants. So, it's not there's not a lot of options, besides the shunt, for most of our patients.

So, I'll talk a little bit about movement disorders. And this is primarily spasticity and dystonia, and then the deep-brain stimulators used for dystonia. So, I'm going to talk about the Baclofen pump, even though it's not part of the ASK CHILDREN Study. It is one of the most common devices we use in kids. And it is, from my perspective, maybe the only device that really where the body habitus of the child impacts our ability to use the device. There's this pump that goes in the abdominal wall, and then there's a tiny catheter that goes around into the spine.

And this child's X-ray illustrates a common problem, in that she has a shunt, which is the thicker tubing, and then she has an intrathecal Baclofen pump. She's also had a spine fusion. And she's had a gastrostomy, too. So, she has all these devices, and you need one or if one becomes infected, it puts the others at risk for infection. It's a big problem to have infection or malfunction, for these kids.

But, the Baclofen pumps do work extremely well to treat these. It improves their quality of life. You have some kids that can gain enough movement that they gain tremendous independence; whereas, before they couldn't run their wheelchair or they couldn't type on the computer, they can now become much more independent individuals.

This or, one of the advantages of the intrathecal Baclofen pump is that it can be used to treat any type of spasticity or dystonia. The dose is adjustable, and there is a pretty strong track record for these pumps, compared to some of our devices, which are perhaps newer, like the vagal nerve stimulator.

This study is from the Netherlands, and the white bars indicate the baseline values, and then the gray bars are the 6-month followup values. And I would also argue that 6 months may not be adequate followup for something like a Baclofen pump. But, even so, on this visual analog scale, you can see there's a marked improvement for those on the left, that were treated with the intrathecal Baclofen, compared to the control group, that's illustrated on the right, in each panel. The first panel shows movement problems. The second panel shows ease of care. And the third panel shows pain. And all of these are issues for our kids with severe spasticity and dystonia.

But, the pump has significant problems. It's very similar to the shunt, in that it requires revisions and it can become infected. And the size of the child often limits our ability to implant the pump. It's difficult to have one safely heal in a child under 15 kilograms. And there's also an issue with: if a pump malfunctions, they can have a life threatening withdrawal. And that needs to be treated by a team that's experienced in Baclofen pumps. And their infection rate is, from my perspective, just a little bit higher than shunts.

Deep brain stimulation is a very promising therapy for primary dystonia. It is makes a dramatic improvement in these kids' lives. The indications for a secondary dystonia -- it's a dystonia from trauma or infection or other etiologies -- is still sort of under review. The causes of secondary dystonia are extremely broad, and the patterns of dystonia are much more varied. So, it's also harder to predict whether kids are going to respond to intrathecal Baclofen pumps for dystonia. But, there are a lot of advantages for the deep brain stimulation. You do have to implant the electrodes into the brain, which can be challenging in some of our kids that have abnormal anatomy due to their insult that they suffered. And this is a big difference between, say, Parkinson's, in the elderly, where they basically have a normally developed brain that's then undergoes degeneration.

But, the deep brain stimulators, similar to the other devices, have to be the batteries have to be replaced. That's not that big a deal. There is a potential for malfunction. There is potential for brain injury, in that there can be hemorrhage or other deficits, and there can be infection. So, they are currently approved, as you heard, under the HDE, for primary dystonia.

And then, for epilepsy, we have the vagal nerve stimulator and the deep brain stimulator. And both of these are piloted devices for children that are not candidates for intracranial surgery. So, by far and away, intracranial surgery gives us better efficacy in almost all of our patients, if they're candidates. But, there are a lot of kids that are not candidates for intracranial surgery, and they do benefit from these devices.

The vagal nerve stimulator was approved for partial-onset seizures. We use it for a whole variety of seizures, and we implant down to 1 year of age, and it works very well in kids. It actually most of the outcome studies show it works better in kids than it does in adults. It's a relatively low surgical morbidity compared to an intracranial procedure, but there are issues that you have to replace the generator again; the lead can break, this lower X-ray shows the broken lead; infection, again, is a problem. And one of the current issues is that they are not MRI compatible, which limits their use, for example, in patients that have brain tumors that have to be followed with MRIs.

The other devices for spine instrumentation and bladder stimulation, there are very few kids, fortunately, that need the bladder stimulators. They do benefit from them, and the diaphragm pacers, the same thing; there's very few kids, but they do have dramatic benefits from that.

This whole issue about, you know, Can the child grow with the device? From a surgeon's perspective, that's not that big a deal or that big of an obstacle. We can deal with that. We would much rather have the child have the ability to receive the therapy and be able to do reasonable clinical trials with the therapies.

The cerebral vascular disorders, the -- our interventional neuroradiologists and neurosurgeons use a whole array of these new toys. And it seems like every year they have a whole new array, which is great, because there are no other options for these patients. So, they should have access to these devices in a fairly unrestricted environment.

And then, I'll just mention briefly, deformational plagiocephaly. This is positional molding. And these little helmets to remold the skull have been classified as a Class II device, with these special protections. And, from a neurosurgical perspective, we really don't think this is quite necessary. The problem with it is that it's increased the cost about 10 times. It's not covered by Medicaid, which is currently about 60 percent of my patients. And so, there is a real and dramatic difference between what we can offer to the children with insurance and those with government or no coverage.

So, in conclusion, I would like to say that it's not only that we have to keep in mind that the children are different, but we have to sort of approach each device and each population differently, and really design the trials and approve the devices, depending on what each disease requires.

Thank you.

[Applause.]

DR. PENA: Thank you, Dr. Robinson.

Are there questions?

Phillip?

DR. PEARL: You talked about shunts being lifelong, but could you discuss that some patients seem to become independent or they compensate for their hydrocephalus? Because the issue of the chronicity of the requirement for the shunt seems to me directly relevant to what this committee is addressing.

DR. ROBINSON: So, there I would say, maybe 10 to 15 to 20 years ago, there was a greater population of babies that had shunts placed, that eventually outgrew them. And there was a sort of a I don't know, a folklore that, oh, if you didn't need a revision by 5 or 10 years, then you no longer needed your shunt. And we know now, very clearly, that that's not true. So, our shunts do last longer. And so, there is a greater population that goes 10 or 15 years, and then they still very much need their shunt.

There's also so, the babies that need the shunts are the greatest populations used to be the kids with spinal bifida and our myelomeningocele repair at birth is somewhat tenuous in some of our kids. And so, there's in some kids, there's an earlier urge to put in that shunt to protect the repair. Now we have, I would say, a little better idea of that we know that about only 70 percent of the kids need the shunt, so that those that do have the shunt now perhaps went through a period of trialing, as babies, and we know now. So, when and the same thing for preterm infants. We have a different paradigm now, that we try to get by with a temporary shunt, and then only those that fail the temporary shunt end up with a permanent one. We, knock on wood, actually haven't put in one for a preemie at Rainbow for 3 years now.

So, the populations are changing. Those kids that have shunts put in now, as infants I would argue, the vast majority of those are going to need the shunts for life. But, the this concept that you you're going to outgrow it, is going away.

DR. PENA: Hunter and Neil and then Kristen.

DR. PECKHAM: Sure. And the that's really nice. I'm interested in whether the experience in the pediatric population, regarding infections, is different than in the adult population.

DR. ROBINSON: So, there is a difference in the infants under a year. So, their whatever, their immune system, something is not as well developed. And so, they are at higher risk for infection. We see that with preemies, you know, whether the other populations have that, as well. But, consistently, across shunt trials, whether they're looking for valves or whether they're putting it in, in the front or the back is better, whatever, you see that trend. So, there must be something there for the infants.

For the older children, the children and the adolescents, I think it really goes along with the other factors that we look at, like nutrition and their overall quality of the immune system. And some of our young kids that really struggle, because they also have CP or they have epilepsy and they don't eat well, or various things, they're similar to our very elderly, where we see the same thing with the DBS for Parkinson's; they're just poor protoplasm to start with. And, yes, they have a higher risk of infection. So, I don't think I think it's the populations, not the device.

DR. PENA: Neil?

DR. FRIEDMAN: Dodie, thank you for pointing out the issue of multiple devices, because I think we have a tendency always, as most studies do, to try and take a pure population, to isolate the population, to look at a single device. And our experience has been very similar to yours when we started look at patients that had both implantable DBS not DBS, excuse me -- VP shunts plus Baclofen pumps; the infection rate was absolutely phenomenal. And those sorts of issues are frequently not addressed when one looks at specific devices.

The second point I would also make is that, often, being able to determine the appropriateness in when to use the devices, we're really lacking in knowledge. And it gets back to the premature population, where if you're waiting for symptoms, as you do in an older child, to develop before you either tap them or put shunts into them, we have no idea what's happening to the brain in the interim. And things like looking at elasticity of brain is something that we're focusing on and looking at now, and compressibility of brain, and what that really does to the surviving neurons and surviving brains.

So, again, we're still at a very, very crude level in the use of devices. And, until we can really look both at the indication side, more specifically, as well as the outcome side, I think there's still a way to go.

DR. ROBINSON: That's a really good point, because in the -- in our very young infants, we have to weigh the increased risk of infection and wound healing versus early shunting. So, there's some European centers that have suggested that early shunting for preemies may be better. But, if a quarter of your preemies are ending up with infection and revisions and et cetera, then that may not be good for the overall outcome, as well. So

DR. PENA: Other questions? Panel members?

[No response.]

DR. PENA: Thank you, Dr. Robinson.

Before I introduce our next speaker, we had an additional panel member join us to here at the table.

Can you introduce yourself? Your name and affiliation?

DR. JALLO: I'm Dr. George Jallo. I'm the pediatric neurosurgeon at Johns Hopkins. And I'm == I thank the thank you for the invitation to serve on the panel today.

DR. PENA: Thank you.

Our next speaker is Dr. Phillip Pearl, division chief, neurology, at Children's National Medical Center.

 

PRESENTATION BY PHILLIP L. PEARL, DIVISION CHIEF, NEUROLOGY, CHILDREN'S NATIONAL MEDICAL CENTER

DR. PEARL: Thank you. I recognize that my departmental appointments are a little bit diversified, but that represents various hats. The music is actually not an error. It's true.

I also should mention I have no conflicts. I don't have a slide about conflicts, but I have no conflicts.

I was asked to talk about the neurological perspective on these devices. But, the way I thought about them although we heard even a better list from Dr. Robinson I sort of think about them as the DBS for dystonia, but that is going to be in -- a future area of growth in epilepsy is direct brain stimulation; then to the cochlear implant as the major focus for this task force; the VNS for epilepsy; then there's the sacral root stimulator for neurogenic bladder, and in some cases for bowel; shunts; and I wanted to add the Baclofen pump, which Dr. Robinson did, and which we already talked about.

So, I thought I'd present some cases. I was asked to give the clinical perspective. I have two cases for you. They're both patients of mine. They're not made up at all.

Case one is a young man, who is 13 in the photograph, and he has a severe form of epilepsy known as Lennox-Gastaut Syndrome. You can see he's quite thin, he cachetically thin, if that's an adjective. And you can see where his VNS device is; we have dashed line. But, what on the right, he has a puncture wound. So, what happened was, this poor guy had recurrent status epilepticus for years and years that actually has gone away more recently, he's about 18 now but at this stage he was 13. He went to a local hospital in northern Virginia, where they did not know him as well as some of the larger hospitals. And, without taking off his shirt, the emergency room physician did not realize that he had a VNS, or may not have been familiar with VNS. So though it's only about 5 years ago, so they were already well known. And this kid had a history of needing intraosseous access for lines; no one could get an IV in him. But, they spotted the VNS wire and thought I guess they thought it was the external jugular, then they just kept stabbing it and stabbing it, trying to get blood, until the mother rushed in the room and pointed out it was his VNS wire and then they got the intraosseous line. So, that was interesting.

And the second case is a older gentleman with a he's now he's 25 in the picture, at least his radiograph 25. But, he had a history of refractory absence epilepsy, with the juvenile absence starting at about age 11. So, he had a -- you know, over-a-decade history of absence seizures that couldn't be controlled with any medication. So, he had a vagus nerve stimulator implanted, which has actually been modestly successful.

But, he was sent in enough to notice something that most of our patients with VNS wouldn't complain about. So, a few weeks after having the VNS, and having it fully, you know, programmed to just 1 and a half milliamps, so not a real high amperage current, every time he turned his head to the right, he felt these electrical sensations, these paresthesias in the left side of his neck, where the VNS was. And since he was a house painter, he had to turn his head a lot on top of a ladder, so he really noticed it. And we worked and worked at it, and brought in an engineer from Cyberonics. And the final decision was

Is there a pointer on this thing? I don't know.

But, anyway, you see, his radiograph says 2a -- panel 2a is what his wire looked like. And the company engineer pointed out to us, what it should look like is closer to 2b, where there's a extra loop for strain relief. Although, our neurosurgeons vehemently felt that they had a adequate strain-relief loop on the left, but the company felt that it wasn't adequate, that it needed to be an additional loop. And the consensus was that every time he turned his head, it caused enough strain on the wire that there was electrical leakage, and that's what he's feeling.

And I just saw him in clinic a couple of weeks ago -- and this has been several years now -- and he continues to have this experience. But, we haven't done anything about it surgically, because his seizures haven't really changed significantly, in terms of getting worse. They may be a little better with the VNS.

The case one, I should say, we interrogated him several times after this puncture, and things seemed to be working okay. But, his seizure control deteriorated about 1 year after this stabbing event. And we had the our neurosurgeon explore the shunt. And, in fact, where the stab wound was, was not problematic. But, around the nerve itself, there was so much scar tissue that that seemed to be the problem, because the VNS was not getting the signal up into the nerve. And it was revised, and he improved a little bit after the revision.

So, that's the story of those two patients. But, what that did was stimulate me to do a study and to look at our adverse-event experience in our VNS population. And I looked at it for about 7-year period, between 1998 and 2005, and I basically defined "adverse events" as VNS-related events that were severe enough that required a change in the therapy, whether it was the programming or actually another surgery. Now, of course, all this was stimulated by that unanticipated iatrogenic event with my patient, trying to get the IV access.

So, these are the results of that study. There were 62 patients at the time in our VNS program, and about 10 percent had drooling now, more than that had drooling, but there were about 10 percent with drooling that was severe enough that we actually had to alter these settings, whether we decreased the cycle period or decreased the current or decreased the frequency, any change or intervention warranted as an adverse event for this study. And then, you can see the adverse events that were there.

I also have a pie chart, on the right, of those patients who actually had to have surgical intervention, not just an alteration in the programming, of the 62. And the 20 of them, about a third of them, had to have a surgical intervention after the initial surgery. And I think this is significant. Now, 12 of those were just routine change of the battery, but the others were not routine, they required removal. And removal, interestingly, in a couple patients, was due to infection, of patients who kept clawing at it. And I think we can we have to work hard to identify, prospectively, what patients are not going to tolerate these things, because they're impaired enough that they're going to scratch and scratch and get infection. So, that's an opportunity for us in this committee. A couple patients had significant enough sleep apnea associated with it that the parents had it removed. One wanted it removed because it just wasn't working.

There was one problem, in particular I was thinking, Dr. Robinson had present about people with multiple devices, and Dr. Friedman mentioned that. There was one patient that was having a shunt revision, and, at the time, the neurosurgeons decided to also do a VNS revision, and the VNS was inadvertently clipped by, actually, one of the neurosurgical residents while the attending was doing the shunt. And so, that was another iatrogenic complication and, I think, a problem in trying to do too many things at once.

Actually, this study was published. The reason I wanted to show this is, I got the cover story of the April '08 Pediatric Neurology Journal. I was telling a medical student, that a actually, a couple of weeks ago, about this article. I said, I felt like it was my equivalent of People magazine, I got on the cover of Pediatric Neurology, at least my patient's radiograph. So, this was published.

The conclusions of the study is that about a third of our patients had treatment-limiting adverse events; the most common were increased drooling and cough. Nonroutine, but surgical, intervention was required in 13 percent of the patients. And unanticipated, but potentially avoidable, adverse events were: clipping of the VNS lead during a generator replacement, during a simultaneous shunt revision procedure; wound infection in impaired patients who were scratching it; dysesthesias as an occupational hazard in a high functioning patient so, who knows how many patients have these patients have these problems, but they just can't describe them; and that gets to the vulnerability of our population and then the misidentification of the VNS wire for IV access in the emergency medical setting.

And one thing I wanted to point out is, since the VNS market has been expanded to depression, with FDA approval, one has to consider the given the prevalence of depression, how important, really, these iatrogenic or unrecognized and perhaps anticipated side effects are. And I think that should be a large focus of today.

So, I started thinking about my clinical observations of these devices, and I talked to our head nurse at our Northern Virginia location, where we have a big outpatient child neurology practice, with a VNS clinic, a DBS clinic, spasticity clinic for intrathecal Baclofen. And I wanted to point out a few challenges:

One is this nonverbal population. Dr. Pena's anecdote of the little girl who said, "Let the air out of the tires," to get the truck through the bridge, is sort of like the Emperor's New Clothes; you need a child to tell you what's going on. So, that's the purpose of the ASK, I think. But, we can't don't really have the child for the Emperor's New Clothes, because this population, for the most part, is impaired significantly impaired. So, our adjustments of our devices are really based on quite subjective observations of caregivers, not of the patient, not of the program.

There's more at stake. You know, it's a lot easier to reverse a medication than a device. And, on the other side of that, there's a tendency, we think, to over attribute adverse events to devices, because once someone goes to the commitment of having a device implanted in their child, then every success may -- you know, one may smile upon the device, but, every problem, one tends to frown upon the device. And we had experiences of overlooking real sources of infection or real sources of altered consciousness that may not be attributable to the device. So, the device adds to the valence of the clinical scenario.

Then, of course, there's body size; that was already discussed. The Baclofen pump requires a certain body size, approximately at least 30 pounds.

As far as the quality of life, I mean, clearly it's a matter of weighing risks and benefits, but I just wanted to reflect on it. There are remarkable benefits. And I the reason I wanted to bring up the Baclofen pump -- and I've mentioned it a couple of times; I asked about it this morning -- one, I was a little surprised it wasn't in the preparatory material. But, the real reason is, it's been such a boon to quality of life. The fact that you can change someone's diaper now, or get them to move because of this thing, is just tremendous. But, then there's this fine-tuning problem. Well, that's actually, it's a good thing. You can actually use a microgram instead of an oral milligram amount of Baclofen, say, to help. So, that's a good thing. But, then we've gotten into problems with overdosing.

The other thing to think about is, the population tends to be the most severely affected patients. So, we're dealing with a difficult population to treat, in general.

When I looked at the committee material, I wanted to mention a couple other items. One is the age extension. Age was brought up this morning in a question, and I have to say, I think it's really important, and I totally agree, that the ages were or, that the age extension was limited was not limited, but was extended from 18 to 21. Eighteen is really just too young for someone to transition into the adult world, especially this population. In fact, the young adults, I find, are one of our most vulnerable populations; they're totally lost in the middle of pediatric and adult care. And it's become the responsibility of the pediatric subspecialists to take care of these patients, in my view. In my view, we should not dismiss them from clinic, ever, as long as we're treating them for the same problem they had since childhood. If they develop a new adult problem, they would be referred at that point. And that's the way I handle it, but not everyone agrees.

The other thing is, we pediatric practitioners are used to off-label work. It's standard to use products off-label. So, any adult approval is going to lead to a rapid adoption of use by pediatric practitioners. And no one should be deluded into thinking that, because something is not approved for a pediatric age, but it's approved and out on the market, that it won't be used widely in children. It will be. So, we have to keep that in mind. And that -- a risk analysis, which was mentioned in the materials, is absolutely vital for pediatric safety -- I think, even in products that aren't going to be approved for pediatric use -- because they're going to be used in the pediatric world.

That was really the end of my presentation that I prepared Saturday. Thank you. But, then Dr. Pena said, "Well, could you talk about CNMC neurology?" And, if I have time, I will. And I'm a little I'm -- I'll just go I'll just blast through this.

I borrowed Hillary Clinton's book title, "It Takes a Village." Not that we're unique. Every major center in child neurology has this approach, I think, that or else it's very difficult to be successful -- where you have this, what we call, Neuroscience Center of Excellence, which ties into a Clinical Research Institute, but our center encompasses neurology, neurosurgery, psychiatry, psychology, physiatry, hearing, and speech. We have a large child neurology department, with various divisions. And I'm just going to each in those division, we have different sections, such as developmental -- for us, as within neurology -- neonatal; we have all these special programs.

I wanted to use epilepsy as an example, because my experience in this arena is really the vagus nerve stimulator. That's my direct experience. I run a VNS clinic; I do the programming actively. In epilepsy alone, we have seven epileptologists at Children's National, here in Washington, with a dedicated epilepsy neurosurgeon and then their fellows and the support staff. And the programs include, not just epilepsy surgery, but medication trails ketogenic diet, vagus nerve stimulator is a program large summer camp program.

So, just as a concluding slide, patient characteristics especially supersede age in neurology. So, these things are mentioned in the handout materials. Weight, body size, physiologic and neurologic development, neuromuscular coordination are all very apt. But, the other main point is the longevity. And this is part of the reason I asked the question about shunts and outgrowing shunts. And I appreciate your answer, because we have to recognize that implanting these in children has longer longevity of the -- and survival of the device than sometimes in adults.

The other thing is, investigators really have to have pediatric expertise and experience. Our special challenges for this day are the population we're using and the fact that these are devices, they're not medications. So, they're less reversible.

And there's going to be future growth in this arena. We heard about growth in vascular disease, there's going to be growth in epilepsy, with direct brain stimulation.

And I thank you for your attention.

[Applause.]

DR. PENA: Thank you.

Questions for Dr. Phillip Pearl?

Neil?

DR. FRIEDMAN: For the just to reiterate your point of I think that we do have to pay a lot closer attention to the fact that there are adult devices out there that are going to be used, and probably not going to get necessarily get pediatric-specific indication. And the question becomes how best to ensure safety within that sort of a population; and efficacy, for that matter.

And, in my small field, we have been using stents, for example, intracranial stents for stroke patients pediatric stroke patients, and we have absolutely no idea what the long-term risks of these are. Clearly, these are in desperate situation and desperate stakes, but once the device is there it is going to be used.

And one of the things, as an aside, adopted at our hospital was -- within our P&T, our pharmacy and therapeutic committee -- is that any drug now that comes into a pharmacy for approval, even if it's an adult-indicated drug, all of them have to go through the Children's Hospital P&T to see if there's any potential use or application, and what monitoring, et cetera, needs to be in place, if that's the case. And you kind of wonder if there shouldn't be some type of a requirement for the FDA to at least have some pediatric protection to any device that's coming out.

DR. PEARL: Yes, I agree. And I know there have been efforts to include pediatric trails before a release of new drugs. I'm not as sure about where it stands with devices, but that has to be recognized, that some sort of a risk analysis should be done for children -- I think, before anything is approved -- since it's going to be used.

DR. SAMUELS-REID: I don't think we got to talk about the entire pediatric guidance, but we do take into consideration risk mitigation for children. And part of the whole "total product lifecycle," that we're working on, is using all of those data from adults, as well as from postapproval studies that are being undertaken, to inform some of the guidance information, going forward. So, that's part of the evolution of what we intend to accomplish from workshops such as this.

DR. PENA: Dodie?

DR. ROBINSON: I just wanted to add to that about the idea that we need to have pediatric protections. But, it needs to be done, I guess, in a very informed way, because, like, for example with the cerebral vascular interventions, we need those absolutely to be available to our kids, because we don't have any other options. Whereas, sort of the other extreme of that is, if you look at DBS that's being considered for psychiatric interventions, or the vagal nerve stimulator for depression, that becomes much, much, much more challenging. And I think most surgeons are quite hesitant to go along that pathway for the psychiatric interventions until we have better definitions of who's going to respond in the adults. So, there needs to be flexibility in those guidelines. I'm not quite sure how to make that happen, but

DR. PEARL: Thank you.

DR. PENA: Dr. Marks?

DR. MARKS: Yeah. I think a big part of that is making sure that, as we're looking at introducing these devices for various disorders, that we have a good understanding of what the natural history of the disorders is. If you look, for example, at the psychiatric application of DBS, they have been limited to patients 18 and older. And some of that is because there's enough variability and enough improvement in psychiatric illnesses before that, that you have to be really careful. And yet, if you look at what's going on, for example, in the world of Tourette's syndrome, where the recommendation has been 25 and older before implant, that is not what most places are beginning to follow, because there's a recognition that there are youngsters with highly malignant Tourette's syndrome that hasn't responded to anything else. And so, you are looking at younger teenagers being seriously looked at for implant.

So, I think understanding the natural history and where you intervene is significantly important. Cerebral palsy is a early-onset disorder in which, you know, after young childhood, significant improvement is really not expected. And then, if you look at genetic dystonias, you actually expect deterioration over time. And so, I think knowing when to intervene is actually one of the big unanswered questions in all of this.

DR. PENA: Thank you.

Other questions?

Dr. Tilton?

DR. TILTON: I was just going to sort of chime in on the cerebral palsy thing. And to recognize that it's a static disorder, but, in fact, you can develop dystonia and other things over time, as well. So, even those things that can seem static to us can deteriorate or change in character from a spasticity to a dystonia, and suddenly that group becomes a group that you wouldn't have recognized initially.

DR. PENA: Thank you.

One last question, Dr. Pearl. You had mentioned, in one of your slides, that 18 is too young to transition into adult neurology. And I'm I was hoping you can expand upon that, sort of, from, you know, beyond physical growth, some of the, maybe, behavioral or other complexities of development that should be considered when thinking about this transition.

DR. PEARL: So, you're referring to the behavioral, psychosocial aspects of that? Is that your question?

DR. PENA: Behavioral, psychosocial, if there's any other maturational changes. I

DR. PEARL: It is impressive how cynical and depressed I find patients with chronic disabilities become at that stage of life. There's a sort of optimism when they're still a cute little kid, you know, and the parents are their advocates and champions. As they get into adolescence -- of course, with any challenge of adolescence life can become difficult with the parent/child interaction -- these patients don't in my experience -- and I haven't done any studies of this -- but they don't seem to enter that adolescent phase until they're really young adults, in their 20s. And then they go through this horrific transition into dealing with their individuality, social relationships, sexuality. It just permeates everything.

I continue I've followed many of these patients into their through their 20s, 30s, 40s, and those issues actually never go away. The I mean, it's for some of them, it's just life of despair. The loneliness, depression and -- these are huge issues. When -- I had tried to transition my those patients into adult neurology, it just doesn't work. They don't get the kind of support. From an individual practitioner, I can't solve these problems, but they still come back. They don't feel like there's a understanding there, on the adult side. This is a terrible generalization I'm making, but it's been my experience with this population. And we somehow need to address this.

Medically we can continue to take care of them; we're not limited. All of us are trained in adult, as well as child, neurology or neurosurgery. But, it really is the psychosocial aspect of it that needs to be addressed. And I don't know about the psychiatry world, but I wonder even if the pediatric psychiatry world is better equipped to deal with this than the adult psychiatry world. I don't know. But, in adult in neurology, it we they bounce back to us.

This is my own personal reflection on at the microphone. If others have something else to say, I would appreciate it.

DR. PENA: Dr. Marks?

DR. MARKS: I think all pediatric neurologists recognize how difficult the transition is from the pediatric world to the adult world. And, actually, at the child neurology meeting was it last year? last year, I think it was, the one of the major award lectures was on this whole issue of transitioning to adult, and the various models that are out there, and whether you know, whether we keep them forever or whether you transition them out. And there are definitely pros and cons to both approaches.

I think the biggest issue, at least if you're operating out of a purely children's hospital, is, At what point do adult physiologic issues begin to interfere with care? Not so much from the pure neurology standpoint -- that part, I agree with you, is relatively straightforward; we are all trained in adult neurology -- but, for people with these implanted devices, at what point is the surgery and the anesthesia no longer appropriate for a pediatric hospital? Do you take a 45-year-old or a 50-year-old who may have cerebral palsy, but now has hypertension, cardiovascular disease, diabetes I know, asking our ICU guys and our anesthesiologists, you know, there's a cutoff there that -- beyond which they don't think it's reasonable and the best care to take care of these in a children's center.

DR. PENA: Dr. Tilton?

DR. TILTON: Yeah, I think this transition issue I'm sure there are meetings like this that are similar, addressing some of that. And it's compounded I'm at a children's hospital, as well, so my children, who are sometimes in their 30s, will go to an adult hospital, get their you know, maybe their device changed. But, the surgeon will only do it if I promise I'll take them back; you know, and I do. And I take them back as long as I can. But, they get appendicitis, and they've got to have three other people on board to take care of them for that.

The other issue is, not only is it the emotional component I think we were talking today about this very issue, and saying that, on an MMPI, that child neurologists are next to social workers, in terms of, you know, personalities, so we're very concerned of the holistic approach. The transition to adult often isn't met with that. And so, not only is there the emotional side, but try to get finances, at 21, to move into other care, and try to talk someone into seeing someone with a different type of payor mix. So, this is a huge issue, but I think, as we look at caring, public health, and issues that relate to these children, it's a very serious issue that needs to be embraced in terms of that.

DR. PENA: Neil?

DR. FRIEDMAN: Yeah, and just to make two points to that, I think the two issues that we see is the one is, you know, the split between the chronological age of a person being in a 25-, 30-, 40-year-old body versus the cognitive age of the person. And there's no doubt that, with all due respect to my adult colleagues, they just really are not in tune with dealing with the adult patient that has a cognition that's perhaps a few years of age.

And the second problem that I think we see is the fact that many of the diseases or the disorders in pediatrics that we are dealing with are not they're not comfortable dealing with that when the transition goes to adulthood. This is being faced, for example, in the congenital heart disease population, where these people are now surviving to adults, and adult heart surgeons and cardiologists are incredibly uncomfortable either going back in to reoperate or even managing them. And we faced the same dilemma, you know, when we had a 70-year-old, the other day, arrest in a children's hospital; it's really not a pretty sight. And but, I don't know what the answer to it is. It but, I think it is a -- it is worthy of consideration.

DR. PENA: Neil?

DR. CHELONIS: With regard to your comment about the psychological development of these adolescents going into adulthood, I mean, I'm a behavioral psychologist by trade, and there's a whole lot of courses in just adolescents at universities, just talking about the adolescent itself, irrespective of childhood or elderly or whatever the case may be. So, I can think of many, many reasons why these individuals may have difficulty adjusting from childhood to adulthood. So, it seems to me like, maybe, like, some kind of clinical psychological help or something like that would probably be beneficial, because there are probably a lot of things that they're not experiencing that the normal adolescent might in these situations. You know, and it might be unique for each individual in these cases.

DR. PENA: Okay. Thank you, Dr. Pearl.

[Applause.]

DR. PENA: I am delighted to say we are on time, to the minute. And this discussion that just occurred might nicely take us into the next two presentations.

Our first presenter, Dr. Neil Friedman, staff physician in pediatric neurology at the Cleveland Clinic, will present.

PRESENTATION BY NEIL FRIEDMAN, STAFF PHYSICIAN, PEDIATRIC NEUROLOGY, CLEVELAND CLINIC

DR. FRIEDMAN: Good morning. Thank you. I'll probably change that. If I'm running too long, just throw something.

Anyway, I'd like to just start by thanking Carlos for the invitation to speak here today, and also for the invitation, really, to be a part of the ASK CHILDREN Study.

I think that this study is really unique amongst devices, in that it's really looking at the impact on the family, the long-term outcomes of these devices, and not just the efficacy of the device itself, as a device, but really what is its effectiveness, in terms of patient care. And it's looking at some unique parameters, such as the psychological, social, physical well-being of these children and the functionality of these devices in these children. And I think that's something that's sorely missed. So, although I know early mention was made that we're not here to really address efficacy of the I assume the reference really is to the device. And what I was to talk about, perhaps, is something slightly different, which is the difference between the efficacy versus the effectiveness of these devices, which has come up while working during this study.

By way of disclosures, I really have no conflict of interest, in context of this particular talk. I must speak on Genzyme, however.

And, you know, it was Mark Twain, or perhaps more correctly Douglas Warner, that made the comment that, "Everybody speaks about the weather, yet nobody does anything about it." I think when you look towards effectiveness of these devices and I think this is not specific for the neurological devices you find reference throughout the literature, and actually throughout the FDA commentaries, about effectiveness. But, when you really try and hone in and find out what exactly are we measuring by "effectiveness," it's really not clear. There's a lot of information that just is not there.

So, I wanted to try and move the conversation forward, if possible, about how we define the effectiveness of these devices; are we asking the right questions; and then, perhaps more importantly, are we measuring the right outcome? Because, I think, with the shifting paradigm, as already a number of speakers have alluded to, sometimes very small functional differences in these children can make huge difference in terms of outcome.

This is a quote from, what most people may know about Victor Frankl, who was a Austrian neurologist, as well as a psychiatrist, and was also a holocaust survivor. But, I think, in essence, what I want to talk about today can best be summarized in this statement. Although this wasn't, obviously, referring to medical devices in children, I think the implication for it is really there: "For the meaning of life differs from man to man, from day to day, and from hour to hour. What matters, therefore, is not the meaning of life in general, but rather the specific of meaning rather the specific meaning of a person's life at a given moment." And I think, when dealing with children, this is something we really have to be aware of, because the goalpost keeps moving and keeps changing, and particularly in neurologically impaired children.

I would argue that perhaps most, if many, if not most, of the diseases that we treat, as pediatric neurologists, are incurable. And really -- the emphasis of our treatments and our therapy is really a goal-directed approach towards management, and trying to either limit or halt the disease progress, where possible, but particularly in trying to reduce the disability, trying to maximize the quality of life for these children, and also, really, symptom management, dealing with the symptoms as they come up, but also trying to prevent complications as they arrive. And I would also argue that I don't think that these particular objectives are very well met, when one looks at current methodology, in terms of research, and particularly in terms of these devices.

The focus, really, is on disability. And when we look at the current devices that are being mentioned this morning, it's really only the VP shunt, as Dodie mentioned, that really is a lifesaving measure. When you look at these other devices, really all of them are aimed at trying to reduce disability. And this is just one definition of disability that I came across, that I really think appropriate and I like to use, that it's "disability is a consequence of a disease that is the result of limitations either of function or of performance or of adaption to life and environmental demands, and very often it's more than just one of these."

The problem-specific, when you look at primary outcome research and pediatric research of chronic diseases and again, this is not necessarily specific to devices, but is very true of devices is that disability, as we've already heard, is really influenced by developmental age. You're taking a child, at birth, that really is nonambulant, nonverbal, not independent, to a child who is perhaps 18, 21, that is really completely independent of all daily activities, and it's really a fluid process. This isn't a process at one point in time. And, although interventions occur at a particular point we may implant a device at a particular point -- if you really want to understand the effectiveness of this device, you really need to look at it over a lifespan; you need to know what happens at different points in time.

The disease stage is very, very important, because our goals change, depending on the disease stage and depending on what we are trying to achieve or maximize from these devices. And the application or the selection of a device for one particular reason may not be applicable 5 or 10 years later in that child's life. And in most of the research that is done really looks at treatment impact -- this is, you know, the biomechanical, the physiological outcome of that child -- rather than really focusing in on functional outcomes, which I think is really the strength and the uniqueness to the ASK Study that's taking the ASK CHILDREN Study that's taking place.

The other thing that was alluded to in the last talk, and I think is really a key component to all this, is that mostly when we're dealing with these children, we really are getting proxy-reported. Now, I know, from this particular study, the reason for focusing on the 17- to 15-year-old is really to try and get the input from those children, and that was said as a particular cognitive level in which the children would be able to participate in that. And I think it's absolutely crucial. However, I think we have to bear in mind that, for the majority of cases of children that we're treating, as Phillip alluded to, that these are children that are really not going to be able to self-report. And so, we actually rely on proxy-reporting. And the family impact was already gone into with the last speaker, so I'm not going to talk about that again.

The pediatric population, as has been mentioned a number of times already, is very unique with regard to certain particular aspects. And we've heard about the developmental side of this, that these task-specific developmental impacts, in terms of motor, social, behavioral, and psychological factors, really do change throughout the course of the child's life. And the need to address pediatric developmental specific and appropriate endpoints is absolutely crucial.

The use of surrogate markers as for endpoints has become increasingly popular among study designs, looking at sort of short-term outcomes and predicting long-term outcomes. The problem is, when you look at surrogate markers in children, and in particular when you look at devices looking for these surrogate markers, they really are not very well defined, particularly in the pediatric population. And the correlation in general, even not in outside of the pediatric population, with functional outcome, is often not really very good.

The impact on which an intervention has on the primary caregivers, versus the patient, can be as important as that intervention on the primary child. When these children are completely dependent and it changes a family's life, it changes the type of house in which they have to live, the kind of facilities they can use, focusing in on the family is not always the wrong thing, even if the child may not get any practical benefit from a procedure.

And then, what I want to spend a little bit of time talking about is the sort of clinical conundrum of really trying to differentiate efficacy, a short-term measurement, specifically as it relates to the devices, versus the effectiveness within this pediatric population.

So, pediatric-specific endpoints is not new, and it's been recognized by the FDA for well over a decade now, and this was from the guidance for industry of clinical investigations. This was actually of medicinal products where pediatric-specific endpoints was highlighted. And, just to quote from it, "The decision to proceed with a pediatric developmental program for a medicinal product" and I would argue the same is true of a device "and the nature of that program involves consideration of many factors." One of the factors that is brought out is the need for developmental pediatric-specific endpoints. And I think this has been mentioned over and over. But, what's interesting, they go on further to talk about efficacy. And, where efficacy studies are going to be conducted, companies may want to develop, validate, and employ different endpoints for specific age and developmental subgroups. I think this is to be lauded. It's a very well made point, but it's also one of the points that affects creativity in device development, because this is really it extends the length of time, extends the population volume that you need for studying these devices, and often is a disincentive for industry. And in pediatric patients with chronic disease, the response of a medicinal product -- and, I think we've heard already this morning, that of a device product -- may vary among patients, not because of the duration of the disease and its chronic affects, but because of the developmental stage of the patient.

The issue of the surrogate endpoint was also recognized a long time ago, over two decades ago now, by the FDA, that we need either clinical endpoints or surrogate endpoints that can allow products to come to market much more quickly and are predictive of ultimate efficacy down the road. The problem, as I mentioned, is that, really, there are not very good markers, when one starts to look at devices, compared to other biochemical or radiographic surrogate markers. And the devices that we are looking at today, I really can't think of very good surrogate markers, in terms of looking at efficacy of these devices, other than doing what the ASK CHILDREN Study is doing, which is really trying to look at functional outcomes from these devices.

We already heard about the Medical Device User Fee and Modernization Act of 2002, and the revision of 2007. But, what I wanted to point out was that the one of the wording here is -- the new provisions of the Act -- was the development of "safe and effective pediatric devices." But, when you read through the paper and you look towards "effectiveness," as it's been described, what they are talking about mostly is the efficacy of the device, really not the effectiveness of the procedure or of the intervention. And again, when you go back and try and find definitions as to

efficacy," as far as outcome, it really is very, very hard to find a good definition for this.

When devices are studied for premarket approval, they usually focus on these very short-term biomedical or physiological outcome, and very often have to do with mortality or morbidity outcomes. However, again, for us, fortunately, in pediatrics, morbidity and mortality are not really key issues. But, the outcomes have only, really, moderate correlation when it comes to looking at health-related specific quality-of-life measures. They also do not measure the burden of disease or the timing of the disease and the impact of that device on that particular process, as I mentioned earlier. And they're often not designed to answer, ultimately, what I think is the most important question, is the clinical-based questions regarding improved functional outcomes, as well as other pragmatic decisions faced by clinicians, and, I would argue, also faced by the families.

So, trials often look to the efficacy of the procedure in isolation rather than looking at it in a real-life context. And Dodie referred to the if you look at infection rates done in trial settings versus infection rate when it gets out into the real world, and these sorts of things, you see that, within trials, we all know that results are generally much, much better than that's going to be accepted out in the real world. And the need for multidimensional outcome tools, as well as improved technology for capturing this, is absolutely crucial, in terms of looking at long-term outcomes. And I would argue that some of this technology is now with us, and it's not yet being utilized the way it should be. And, because of time constraints, I'm not going to talk about it. But, in particular, with the electronic medical record, I think our ability to capture a lot of these endpoints and these markers provides an incredibly unique opportunity.

I'll just very quickly say that, at the Cleveland Clinic now, within the Neurological Institute, no patient comes through the Institute without filling out some quality-of-life or outcome questionnaires as it relates to every single disease process that they're going through. And this is captured electronically with data points that is easily searchable and recoverable. And I think this is something that needs to be emphasized for future trials and designs, especially in terms of long-term outcome.

So, this is a quote from a paper by Lin, et al, who very specifically was looking towards pediatric cochlear implants. It was a review of the pediatric cochlear implant and, I think, better than I, can really emphasize this difference between clinical efficacy versus functional effectiveness. And just to read the treatment impact component of this, "It's unclear how clinical measures of efficacy example: hearing and speech measures, which is usually what the outcome is for a device manifest in actual effectiveness, which is really the performance in home, school, social setting. How does the child do once that device is in?"

And I think we can learn from epilepsy. The focus on epilepsy, a few years ago, had been the ideal focus was complete seizure control, and we very soon realized, particularly in the pediatric population, that wasn't always a realistic goal. So, people started looking at seizure reductions. And one of the measures was whether a drug could reduce seizures, or a vagal nerve stimulator could reduce seizure, burden by about 50 percent. Well, that's all good and fine, and some people are seizure reduction of 50 percent may be fantastic. If you're having 20, 30 seizures a day, and you reduce it down to perhaps 10 or 15 seizures, that may have a really direct impact, in terms of the child's development and child's well-being. If you're having some of these children with -- that Phillip alluded to, maybe having hundreds of seizures a day, if you reduce them down to 50 seizures a day, ultimately it may have no practical effect, in terms of outcome for that child. So, even though you can show that reduction, whether it's through a device or whether it's through a drug, it really isn't impacting outcome.

And we've heard already about the issue of dystonia and cerebral palsy. And this is an area that I think is again, speaks to the fact that we have to start thinking outside of the box when it comes to these devices and the use of these devices, in terms of measuring different levels of outcome. When you look at DBS and you look at its use as a primary indication for dystonia and its primary indication is in the primary dystonias, really what they measure, in terms of outcome, has to do with rating scales that are really very practical, functional rating scales to do with dystonia.

The one that's listed here is sort of the common one used in the adult devices. There are pediatric modifications of this. But, as you can see, it really is just looking at the dystonia and what happens to the dystonia. None of these studies have really looked at what the functional outcome of these children were. What is the symptom control? And I forget which of the speakers put up the graph showing that, when you put in these devices, how pain control, how comfort control, how diaper control, how very practical things can be dramatically impacted by even small little changes. And the restoration of certain lost function, however small it may be, if you can take a child with dystonic cerebral palsy and allow them the ability to have some control over the use of their hand, their ability to use a manual wheelchair or their ability to use a communication device is world-changing in the life of that child and in the life of that family. And, unfortunately, none of the measures that we look at really get at that. And I'm certainly hopeful that -- this is the first step with the ASK CHILDREN Study -- that this will become part and parcel of device approvals in the future.

And then, with all due respect to Dr. Marks, sitting in our audience today, I've lifted this straight out of a paper he wrote last year, but I think he very eloquently highlights this point better than I can. And he is referring here to they have a very wide experience broad experience there in the use of the deep brain stimulators for, sort of, secondary dystonias in control of dystonias. But, the point made by Dr. Marks is this, that, "The total scores" excuse me "The total scores are not an adequate reflection of the often small, but important, functional changes that may significantly improve quality of life," and later on goes to, under the discussion, talk about that, "Even these small functional gains in the extremity, without a fixed deformity, may significantly improve the quality of life." Just saying more eloquently what I was trying to say a minute ago, about the need to look at the long-term effects of these devices.

So, in conclusion, then, perhaps more questions, again, then true answers. But, I think it's very important to get at this point of, How do we then define "effectiveness"? And I think it's very hard to try and summarize it or define "effectiveness" in a very nice, neat, short, simple sentence. But, I think there are a few components that go into defining "effectiveness," and that, when we look at the device the devices or -- whether it's medicinal or devices -- that these are things that need to be considered for future.

The first is the need to identify the pediatric-specific measurable endpoints, but also appropriate outcomes that have correlation with clinically relevant outcomes. This is things like functional capacity outcomes, quality-of-life outcomes, and longitudinal outcomes relevant to developmental age.

The third point here is frequently mentioned and cited, which is the development the developmental age aspect, but the other two is really not that well described or well informed. And I suspect John's going to speak at least to some component of this in the next talk.

Again, the FDA recognized, in one of their previous workshops, this need for collaboration between the clinician, the scientist, and the targeted population. And again, I'm really pleased to see that, with this FDA ASK Study, the incorporation of the end user; that is, the people who are affected directly by these devices, and not just the medical community and the scientists. And I think that we need to store ensure better involvement, overall, of parents or children, when appropriate, in selecting those outcomes that we need to look at and that really do impact quality of life.

And then, the question's already been raised about, you know, How do we define these surrogate endpoints, especially when there aren't any out there? And what's the risk/benefit ratio? And I think that we really have to be able to or be willing to assume higher risk in order to establish some of this effectiveness.

These procedures, these devices, certainly carry with them risks. We've heard about the complication rates. But, it shouldn't be over emphasized that some of these small functional changes, which we have a lot of trouble measuring at the moment, cannot be measured through very simple surrogate endpoints.

And, ultimately, the hindrance to device development lies within this. Clinically relevant outcomes really require longer periods of observation and follow-up. It becomes an economic disincentive for the companies that are doing this, and even for the scientists working on this, because it's something that you have to stick with for many, many years. There's, again, a relatively small market potential for pediatric devices. However, again, I would say that if one starts to think outside of the boundaries of what we're trying to achieve, you know, taking a scale reduction or taking a dystonia scale reduction, but you're, rather, looking at function, I would argue that if the device companies start looking towards, for example, the cerebral palsy population, there's a huge market that's out there that may potentially benefit from these devices. And if they can be made much safer and much easier to use, I think that their influence on these children will be much that much greater.

And there are also a smaller number of eligible pediatric patients with specific clinical conditions in the clinical heterogeneity of the population. That's something that's also been alluded to through some of the morning talks, but I think is an absolutely key component. Even though we're looking at these devices in a group of children and for specific indications, the truth of the matter is, even within that population, it is extremely heterogeneous and that no one single measure is going to be applicable to all of those children. So, when we put in shunts, some children have just simply hydrocephalus. Dodie showed a tremendous picture of the reduction of hydrocephalus of the brain coming down after the placement of the shunt, but I suspect she and others here have all seen the situation where you do that and the neurological outcome -- not the lifesaving measure, but the ultimate neurological outcome of these childs is no better. So, even though sometimes these devices can have dramatic effects, the outcome is not always the same.

The neurodevelopmental status is also very, very difficult to assess, and also costly to measure reliably. And, as I've mentioned, there's a longitudinal study -- requires repeat assessments in order to get maximal validity from these studies. And again, the need for this improved less labor-intensive tool for validating these outcomes will really facilitate these sorts of research projects.

And again, I'll turn to the electronic medical record, and the utility of it, and the ability of it to look at these postmarketing outcomes, because I think there's an incredible resource there that we are just starting to work with, but has already helped us, not only to identify potential complications, which is where a lot of the postmarketing followup has really had focus -- is in the adverse affects -- but really some of the questions that need to be focused on and addressed.

So, I thank you for your attention. I'll be happy to take any questions.

[Applause.]

DR. PENA: Thank you.

Any questions for Dr. Friedman?

Dr. Pearl?

DR. PEARL: Your very nice, Neil -- your comment on short-term outcomes being what's seen in studies, prompts me to ask about the ASK Study. So, the inclusion criteria were for patients who had had the devices less than 12 months. And I'm sure there were good reasons for that. But, it seems to me that misses a treasure of data from people who have had these devices in much longer. And I realize that'll be collected prospectively. But, it seems like there ought to be a study that includes these people who have had these devices for years, because that is that's the big area of morbidity, I think.

DR. FRIEDMAN: I guess I'll turn that over to you, Carlos. I'm not sure

DR. PENA: Okay.

DR. FRIEDMAN: what the

DR. PENA: I think when we first designed the study, we were trying to focus in on a very defined population. We wanted to target children and adolescents who had just received an implant or a device, and we were trying to evaluate those considerations that would best get them back to either their normal way of life at home and at school. So, we included even if there was an adjustment made, because the thought was, well, if they got the device or they had an adjustment, we want to make sure that we understand those considerations, in trying to get them back to their normal way of life. And that's why we sort of capped it at 12 months.

Now, I understand that the observation that you made, there's a lot of other data that could be collected. I think that's definitely open for discussion; it's just that, you know, it's a very small study. We tried to design it as best as possible, as a first step in, maybe, looking at, maybe, larger expanding areas of future studies.

And Dr. Eydelman?

DR. EYDELMAN: I just wanted to make some general comments, in light of Dr. Friedman's talk, which I enjoyed very much, by the way. Thank you.

FDA only well, FDA only regulates devices and not medical procedures or the practice of medicine. We are very, very interested in understanding how the device affects the whole individual. So, the clinical trials for neurological and neurosurgical devices that are underway, the endpoints that we find acceptable tend to be not just tend to reflect the impact of the device on the condition that it is intended to treat.

Also, the quality-of-life issues are becoming a significant part of our clinical trial designs. As a matter of fact, there's a patient-reported-outcomes guidance that was just issued, not long ago, which clearly delineates what the FDA's looking, in the patient-reported outcomes and the use in clinical trials. And we encourage all of the sponsors that are currently under IDE, or Investigational Device Exemptions, to incorporate as many pros of patient-reported outcomes in their clinical trials so that we do understand the perspective of the patient, in addition to the physician or the caregiver.

The other point I wanted to make is, we are here to get devices to market as soon as they demonstrate reasonable assurance of safety and effectiveness. Hence, while we would all conceptually like to have 10-, 15-year trials, I don't think the patients or the or you, would like to wait 20 years for the next device to get to the market. So, it's always the hence, my picture was a scale -- we always decide when is there enough to say that we have reasonable assurance of safety and effectiveness.

Having said that, long-term outcomes and the effect in general population, which I agree with you tend to be very different than in the very idealized situation of clinical trials, with the best investigators, best surgeons, et cetera, are becoming very, very commonly studied in our postmarket arena. As a matter of fact, for all of the PMAs for all of the postmarket for all of the submissions for Class III devices, we expect each sponsor to have a section that addresses postmarket study; i.e., either give us a very, very good reason as to explaining why their particular device does not need to be studied after it gets to the market, in a postmarket arena, or right away propose to us a study that will identify that will delineate how the issues which weren't fine-tuned, premarket, will be addressed. And then we take that information, eventually, and feed it back to the labeling.

Going back -- since I got the mic -- going back to some of the comments that Dr. Pearl made earlier, I very, very much agree with the concept of in an ideal world, we would love to see every device studied in a patient in a pediatric patient population, even if it's intended to be indicated for adults. Having said that, we only review what gets submitted to us; hence, if the indication for use is for adults, we study the we review that submission for the adult indication, and usually put some warnings or precautions in the labeling, addressing the fact that this was not studied in pediatrics.

However, I really would like to encourage the academicians and professional societies that are represented here to take an initiative of, even once the device is out and indicated for adult population, you are the ones who really should be the driving force in trying to get the sponsors, or doing it as a under professional organization or some other venue, to study these devices in pediatric population, if you truly believe that they will be used in pediatrics.

Thank you.

DR. PENA: Thank you, Dr. Eydelman.

Other question, comments?

Dr. Marks.

DR. MARKS: Thank you for that very nice summary, because I think really understanding efficacy versus effectiveness or is critical to our understanding of what's going on.

The only thing I would add is that, you know, we're very interested and very focused here on how it affects the child, but children don't live independently, and much of this is really has to do with the family. And some way of assessing caretaker burden, I think, is critical, not only in how to fix their quality of life, but it has a huge economic impact, in terms of workdays lost, workdays gained, the evolution of health problems in the adult caretakers of these children; and whether they can remain at home, whether they you know, whether they live independently, whether they remain at home, or would they end up in some type of facility, ultimately has a huge economic impact on everything.

And I would really see, now that I kind of understand what's evolving here, that there is a role for the FDA, I think, in looking at these quality-of-life issues and sort of the next initiative from this retrospective, "ask the children," you know, remembering what your life was before the device which is a good reason for limiting it to a year, because, much beyond that, they're not going to remember what their life was like to prospectively getting an assessment of what their life is like now, and then following along for a period of time, compared to other children that don't have these devices or have different interventions.

And I understand it's hugely complicated and very expensive, but, as best I can tell, there is no really good quality-of-life measure out there right now. And I think the maybe one of the key roles of governmental organizations may be actually to help guide the development of a good quality-of-life measure, or series of quality-of-life measures, that can be looked at and utilized in some standardized fashion.

DR. FRIEDMAN: I think, hence, the current focus on what is being referred to in the literature as health-specific or health-related quality-of-life outcomes, I think, is absolutely key.

DR. PENA: Okay. Thank you.

I think we're going to have to two more questions and then we'll make sure to go to the next speaker.

Dodie and Ann.

DR. ROBINSON: Well, I'll just be quick, but I just wanted to echo that we need to look at this prospectively, because we have several families where they may have a device implanted and that they go on for -- say, they have their pump, and it works great, and they go on for 5 or 7 years before they ever have a problem, and then all of a sudden it really dawns on them the change in their life that they've had. So, they've gradually accommodated to it. And so, I if there's some way to do it, that every kid that has a Baclofen pump gets followed, that is not I can't conceive of how we, as, say, pediatric neurosurgeons, have any mechanism to follow kids. They move, they change insurance and they move different hospitals. If there was a reporting form that had to be filled out every time you replaced the pump or the VNS generator, or whatever, then maybe we could collect some of this data prospectively. How many problems have you had? What's the major change and impact? And I don't know of quality-of-life scales that measure, like, it only takes 5 minutes to change the diaper instead of 30 minutes, but we -- that's the kind of scales that these people need.

DR. FRIEDMAN: I think that it can be addressed, again, just to keep harping on it, but I really do believe this can be addressed through the electronic medical record, as well as the portability of healthcare. And I think that, this day and age now, there's really no excuse why medical records should not be portable, through the electronic medical system, why you should not be able to move your care from one institution to another. And yet, those data points are not available to you. I think the technology is there, I think we've just been very slow in getting to it. And I think that, again, we're just in the earliest stages of this, and it's pretty remarkable, the data that you can capture, if you're ready.

The problem is that some of the validation scales, which has been alluded to, some of the outcome scales asking the right question is not there. So, when you ask a standard quality-of-life for children across a hundred different diseases and a hundred different stages of diseases, it kind of gets lost in the water. That's what we are battling with at the moment.

DR. PENA: Response from Dr. Eydelman, and then a question from Ann, and we'll move to Nick.

DR. EYDELMAN: Just two comments. As far as validation, I absolutely agree with you. And actually, our pros-guidance gets into this, that the question is only validated for the population in which it's validated. But, the National Institute of Health has been very, very involved in other arenas -- not in the pediatric neurological devices, but, for example in ophthalmology -- has been incredibly involved in validating questionnaires for specific disorders. There's a -- one government agency that has the funding and the resources and the expertise, sort of, to put together the panels. So, again, I urge you, as a society, to perhaps proceed in that direction.

Now, as far as Dr. Robinson's comment earlier, one very effective way to deal with the issue you're describing is a registry. And again, this is not a novel concept for us. We have worked very closely with other professional organizations that have created registries to capture particular information to answer specific questions. And, as a matter of fact, we have a whole division, within our Office of Surveillance in Biometrics, that is dedicated in helping people organizations that want to put together registries to address specific issues in the way that the organization will get helpful information, as well as FDA, so that, at the end of the day, we can use some of the data from the registry and perhaps affect the devices that are either on the market or going to the market in the future.

DR. PENA: Dr. Chilton?

DR. CHILTON: Two very quick comments. One is that the patients really do forget what it was like before the devices. And so, getting a marker and then following it, usually you find that when something goes wrong and they think they're worse than they ever were before, and you that's the value of video; we take it back and go, "Oh my gosh, they're back to baseline."

The other thing, just on disability -- and you may have already incorporated this -- WHO, for the international classification of disability in some of the newer models, actually break this, sort of, quality of life down into multiple different levels that you can sort of, you know, figure out, in terms of testing, such as participation, activity, environmental, and all those other sort of aspects of disability. And that's sort of an evolving field. I co-direct the rehab unit, although I'm a child neurologist, and those sort are the sort of the sort of things we also look at. And so, it's not the globe of quality of life, but maybe how they participate, not only just the disease process, but each level all the way up, which may be helpful, in terms of defining some of your outcome measures. Although, it's a huge group and I totally agree.

DR. PENA: One very quick question from Hunter.

[Laughter].

DR. PECKHAM: I just want to note that the National Institute of Child Health and Human Development has a center called the National Center of Medical Rehabilitation Research who has a -- an -- a significant focus of their activities, of course, are related to this. And I wouldn't be surprised if we could, you know, find interested investigators who could come together and write a very interesting grant proposal to them that would be looked at very favorably.

DR. PENA: Thank you

Thank you, Dr. Friedman.

Our next speaker is Dr. John Chelonis. John Chelonis is at the University of Arkansas for Medical Sciences, Arkansas Children's Hospital, and he's also with our National Center for Toxicological Research at FDA.

John?

PRESENTATION BY JOHN CHELONIS,

UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES, ARKANSAS CHILDREN'S HOSPITAL, NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH, FDA

DR. CHELONIS: We don't have this kind of technology in Arkansas.

[Laughter.]

DR. CHELONIS: Oh, there's everything. Okay, it's all hidden. Thank you. Okay. I just didn't see it. All right.

Okay. So, as Dr. Pena mentioned, I'm with the Arkansas Children's Hospital. I'm also with the Food and Drug Administration. Andrea Sutton's my project coordinator, who assisted me with parts of this presentation.

Can everybody hear me okay? I tend to wander around a lot, and I speak pretty loud. I'm used to teaching Intro Psychology, where you have 500 half-asleep students in about this size of a room. So, I'll be wandering around and yelling quite a bit.

First off, though, it's kind of interesting I'm hearing these discussions. My background is in behavioral psychology. So, I'm probably way different than most people in this room, as far as background. And I think, as a behavioral psychologist, I can probably add a few things that might be some issues that might come up, or maybe help resolve a few things here or there, perhaps.

I want to mention, too, that I've worked with various species, such as rats, pigeons, monkeys, childrens, adults, elderly, et cetera, et cetera, et cetera. And I'd like to tell you a little story about some animal research that might be relevant to some of the problems we're having here today. I didn't do this, this is before my time. But, some of you remember -- may remember, back in the late '50s or early '60s, they were interested in language in animals. And what they wanted to know is, Can monkeys produce language like humans? I mean, they're cognitively fairly similar. One would expect them to have the mental capacity to perhaps do this.

So, after throwing a lot of money at this, two researchers raised a chimpanzee. And what they did was, they tried to get the chimpanzee to talk. After much research and much money, the chimpanzee learned four words: "Mama," "Papa," "Up," and "Cup." And from that point on, and from the '50s until the early '70s, chimpanzees don't have the cognitive ability to speak. Humans have a unique ability for speech that these animals don't have.

Well, it turns out the problem wasn't so much the speech, the problem was, the animal didn't have the larynx in the proper place to form vocal sounds. When they started using sign language, it's amazing the number or words these chimps can learn. Now, granted, I'm not going to sit there and have a conversation about the meaning of life with any of these chimpanzees, they're not quite at our level, but the point is that it's how you ask the question that's important.

The animal literature and the developmental literature in human psychology are riddled with things that we know now, that we thought were impossible 5, 10, 15, 20 years ago, because we didn't ask the question in the right way. And in hearing some of these discussions, I think part of what we really need to be figuring out here is, How do we ask the question? And, I think, that's part of what I'm going to try to talk about today.

Okay, I just pushed a button and everything bad happened. You say the down arrow? The up arrow.

VOICE: There we go.

DR. CHELONIS: Now, which button am I pushing?

VOICE: Right arrow.

DR. CHELONIS: Oh, okay. So, it was the right arrow, then. All right. Okay.

So, first off, disclaimers: I have no financial or benefit or anything from any of this. I'm an FDA employee so I have the opinions expressed are mine, and not the FDAs. And I will be expressing opinions.

Okay. So, as we all know, one of our problems here is trying to figure out risk/benefit ratios. So, obviously want more benefit than risk. It's easy in cases of physiology or life-and-death situations, obviously. I'm alive, I'm not dead; I think that's a pretty huge benefit.

The problem is, though -- this gets to be complicated, though, when we start dealing with the quality-of-life issues. So, for example, What is the unit increase for quality? How much more quality gives us a unit increase in this situation?

Also, too, as we've been batting around for pretty much most of the morning, How do we measure quality of life? What are some of the issues we have to deal with in these kind of measurements?

So, for our ASK CHILDREN Study, we have some secondary study outcomes. We're attempting to measure quality of life. So, first off, we're trying to determine the feasibility of these instruments to measure the quality of life and outcomes. So, are these instruments feasible?

One thing I want to mention is, the ASK CHILDREN Study is not the be-all and end-all of research. I can't think of any, really, study that just, you know, one study that all by itself says, "Okay, here's the answer." Research builds on itself. So, hopefully this will kind of and it sounds like it is, initiating more research projects down the road to say, "Okay, here are some instruments we might want to use, let's tweak these, let's take what we've learned, let's add to it, let's discard some things we learned we shouldn't do, et cetera, et cetera, et cetera."

So, we're trying to get at physical aspects of quality of life, external behavior, and emotion. I'm going to be focusing mostly on external behavior, because that's more of my area of expertise.

One thing that this study works on is, it uses multiple assessments to get at aspects of development. So, one problem that a lot of studies have is, they usually have one or two, maybe, measures, and that's about it. Here, we have a whole wide array of measures, which will hopefully help get at some of these issues.

And, of course, then we are looking at both quantitative and qualitative approaches here. So, by quantitative, they tend to be, like, yes/no answers. You can quantify it. Qualitative, on the other hand, is going to be more kind of freeform responses. And I'll kind of talk about some advantages and disadvantages to both methods of looking at behavior.

There we go. In fact, I guess I'll do that right now.

So, qualitative. The advantage of looking at qualitative things these are open-ended questions, such as, "Has your life improved?" or, "How are you doing now?" or things like that. And they allow for novel answers to questions. Unfortunately, our research assistants don't like them very much, because they have to sit there and scribble as fast as they can as the person's kind of free-associating. But, they do allow for novel answers.

They also allow for very detailed answers. So, you get some children who want to talk a lot about these different devices, and tell you how they could be improved, and, "Wouldn't it be neat if there was, like, a little radio transmitter in here, where I could listen to music?" or things like that, for their cochlear implant. So, you get a lot of these kind of interesting, novel approaches to things.

The disadvantages are very difficult to analyze. You can't combine data and look to do statistical analyses or things like that.

When you have quantitative approaches, however, these data are very easily analyzed. You can clump them into different groups, assuming you're asking the right questions. You can easily see similarities and differences in your answers, and you can group them accordingly. The problem is, though, with this case, the answers are only as good as the questions. So, if you don't ask the right question, you're not going to get any kind of good answer. Whereas, a qualitative, if you can ask a question, hopefully you can generate some kind of answer. But, then again, they're difficult to analyze.

So, some of the measurements issues that were occurring in the ASK CHILDREN Study, and it sounds like in pediatric psychology in general, trying to look at this stuff, is, we have to deal with development. You've heard it 100 times; you're going to hear it 100 times more: Children are not little adults. You've got to deal with these developmental aspects.

Also, too, children's quality of life, they have different issues than adults do. We have to deal with the home; we have to deal with the school environment, friends. There's things that are important to children that aren't necessarily as important to us as adults.

This is that monkey question again. We need to kind of start keeping that in mind. I mean, I know it's hard for some of us, especially as we get older, to think like children. But, that's always the key in the animal literature. You know, we try to think like the pigeon. Okay, what's the pigeon going to do in this situation? Well, the same thing here. Think like the children. What's important for the children in these situations? What issues might they have? Because they may be very different than things that we think are important. And, of course, then these issues may affect these kind of outcomes. So, what kind of issues do the children have? How are they doing in school? How important is it to have friends? Et cetera, et cetera, et cetera.

So, with regard to development, then, physiology and behavior are relatively stable in adulthood. At least we hope it's relatively stable, because our only option besides that is slightly downhill. Also, too, assessing outcomes in children, we need to take development into account. That's not necessarily important for us as adults. One nice thing that's been brought up in the previous presentation is the idea of: multiple assessments might be helpful here to kind of plot developmental rate. Taking a snapshot in time may not be the best approach here. Maybe it might be better to take several different snapshots across periods of time, to look at this kind of rate of development and compare it to that of children without the devices or children who don't or normal children, who don't need the devices or perhaps children who have a different device.

Now, for all you pediatricians in here, I apologize for this graph. I know that nothing developmentally goes linearly. I know you have little spurts, and ups and downs, and things like that, but this just makes my demonstration a bit easier to demonstrate here.

So, for example, here, if we look at some kind of assessments, let's say we have normal development in red, treatment in blue, and no treatment in green. If we look at children at 4 years of age, what we see here is that the treatment group shows a slight deficit compared to controls, and they're doing slightly better than no treatment. Well, what happens is, this rate of development is different, so you start seeing larger differences as these kids get older and older and older. This is where the comment by Dr. Pearl about these adolescents comes in, because at that point, you know, they may be going at different treatment speeds, you're going to see huge differences as they get out to 12 or 16 years of age.

I should mention, as well, too, thinking from a psychological perspective, there's often a lot of critical periods that occur. And sometimes these devices may not allow these children to experience these critical periods normally, like another child might. So, for example, think about, kind of, adolescence. That's our time when we start to assert our independence. In these types of situations here, I mean, if you've got some kind of implant, it may be difficult for you to assert your independence in that situation. I mean, you can't rebel and say, "I'm going to stay out til midnight and take the car and, you know, go out and hang out with my friends." That's not really something you can necessarily do, depending on what kind of device is implanted. So, you might not have the chance to develop that independence, for example, that another child might have. And, just thinking about developmental literature, there's all kinds of different critical periods where children may miss them or they may not experience them in the way that another child might.

So, we can assess the quality of life quantitatively. In fact, our ASK CHILDREN Study attempts to do that. We have something called an "activity scale for children." This is nice, because it's fairly straightforward. I mean, Can you walk down stairs? Yes or no. Or more importantly to me, Can you make a snack? Yes or no. Well, that's nice. But, once again, though, the problem is, this may not apply to every child. Maybe some things, like a cochlear implant, may not affect your ability to walk down stairs or make snacks. You can do it whether you have one or whether you don't; whether you can hear or whether you can't. So, the problem is, trying to generalize this thing across the board can be difficult. So, specific scales for different disorders might be useful here.

And, of course, then we can assess things qualitatively. How's your life improved over time? Or whatever.

Either way we measure things, though, there's things we need to keep in mind when we're doing these assessments. One of the important things is context. So, let's say everybody over here at this side of the room, you're all making $100,000 a year, okay? Wonderful. Great. Life is happy. I'm academic, $100,000 a year sounds great to me. So, you're all making $100,000 a year. You're all life is happy, life is good. You can do what you want. But, one day you all find out that they're making $200,000 a year. Is life still happy? Probably not, all of a sudden now you feel ripped off. Life sucks. That's not good.

So, the point I'm trying to make is, a lot of times children compare themselves to their peers, especially when they get older. So, it might be a situation where, "Okay, I'm doing fine, doing fine." But, all of a sudden I realize now, "Hey, it takes me 2 hours to get ready in the morning." "Hey, I can't hear like the other kids can hear." And when they start comparing themselves, you start to get context effects. And you see this a lot in the psychological literature.

So, one thing we need to start taking into account is, What's the context here? How much interaction do the children have? So, for example, a child who's in a special school system with a lot of other children who have disabilities and other things going on, they may not feel quite so out of place as the child who might be trying to be mainstreamed into the main school, who may be made fun of, or whatever the case may be.

Another thing to keep in mind, too, is, not only are we affected by our context, but we're affected by our previous experience. In the animal literature we call this "behavioral contrast."

So, let's say, for example, you, over here, you're making widgets, you earn $5 a widget. Okay? You, back there, you're making widgets, you earn $10 a widget. You guys make more widgets than they do, because you're more motivated to do that. However, I bring you all up, now, to $10 a widget. I increase your wage. For a while, you'll make more widgets than they will. Because what you do is, you compare what's happened now with what happened in the past. So, all of a sudden you got a raise, so your widget production will actually rise above theirs. Eventually it'll level off to theirs, but the point is, though, you start to compare what's happened in the past with what you're doing now.

So, the problem is, these things aren't always it's hard to measure these things objectively, because they're not always objective. They're dependent upon our context and who we look at around us. They also depend upon what happened in the past. And this could work in reverse. If you get downgraded, or whatever, you might have a worse feeling. Okay, I was doing really well before, now all of a sudden I'm not doing so well, so you might have an over-compensation regarding your feelings, based on going down, in that situation.

So, general issues when assessing parents. Oftentimes, even though this is the ASK CHILDREN Study, it's good to ask the parents, as well. Because parents don't often remember or children don't often remember a lot of things about their medical devices -- what brand is it, when was it implanted, things along those lines. They're really bad at these kind of medical issues, especially if they had it around for quite some time. Also, too, children can be somewhat shy. Some children are more reluctant to share personal information. So, when we assess our children in our study, in our site, you know, it's nice to have the parent around, because they will often say, "Well, you remember that one time when," or they might add a little bit of extra information here. So, although the children do a lot of the talking, the parents are good to kind of interject and add information here.

But, of course, having children and parents around, though, you sometimes have difficulty with what we call inter-rater reliability. We see this in the clinic a lot when we're dealing with psychological disorders, where more information is not always better. So, for example nowadays and this is especially true -- let's say I ask, you know, little Susie or little Jimmy, over here, "How many friends do you have?" And Jimmy says, "I've got a lot of friends." Well, you go and you follow up with the parent, "Well, how many friends does Jimmy have?" "Well, he never stays after school, he never has anybody over. They're all cyber friends." Is cyber friends a friend or not? I don't know. You know, you miss out on some of that social interaction. So, one of the problems is, you know, if Dad or Mom says, "No, they don't have many friends. They're socially isolated, sitting in front of their computer all the day," whereas little Jimmy thinks he's doing fine, he's got hundreds of friends, more than any of us probably ever had.

Another issue, too, is internalizing versus externalizing. This is another issue we have to deal with a lot here. Children are better regarding internalizing. And what I mean by that is, these are things like emotions, like depression or things like that. Whereas, externalizing deals more with things like, you know, disruptive behavior. I mean, let's face it, how many kids are going, "Yes, I'm a jerk. I'm at school, I can't get along with anybody. I run around and I cause a lot of trouble with the teacher"? How many kids are going to admit that? Probably not very many. Parents will be more than happy to, though. So, this is one of those situations where externalizing behavior is probably better when you start assessing it from the parents' point of view, because they're going to be more than happy to tell you what's wrong with their kid. Whereas, internalizing behavior, oftentimes the parents don't realize their kids are depressed or sad or whatever. So, in that case, oftentimes it's better to assess children, in that situation.

Also, too, the wording of the questions can be very important, so we can often create some kind of bias when answering questions, depending on how we deal with the questions. Open-ended questions, such as, "What do you like about, or what do you not like about, things?" tend not to lead to too much bias.

But, there are some interesting studies done in the area of eyewitness testimony. Dr. Elizabeth Loftus did some work, where what she did was, she showed people a picture of a car accident. And they saw the picture, and they looked at it for a while, and then several days later she asked them a question. Was there any "You remember the picture where the two cars smashed into each other? Was there any broken glass?" When you use the word "smashed," they tend to think that there was broken glass. However, if you ask them, "Do you remember the picture I showed you a few days ago, where one car hit the other one?" You're less likely to see broken glass. So, a lot of times you know, less likely to think you saw broken glass. There was no broken glass in the picture, but just the use of words can influence performance in these situations.

So, we've got to be careful, when we assess these children and these parents, that we don't lead them into saying, "Okay, this medical device is horrible," or, "Okay, this medical device is great." So, you got to kind of watch that kind of stuff.

Now, if you do things like assess the ability to perform specific behaviors, such as getting snacks or going down stairs or stuff like that, you're not going to have these problems. When you start getting more, kind of, quality of life, or, "What do you think about this item?" or whatever the case may be, that can be where you can get in trouble if you don't watch out how you're assessing things.

And one thing that's been kind of hinted at, and I want to stress this as well, studies have shown that a strong support system can greatly enhance outcomes in a variety of psychological disorders. One of the things we learn in clinical psychology is, a strong support network is a very good prognosis for getting better, whether it's depression or schizophrenia or whatever the case may be. And I was kind of finding and kind of hearing -- I think that's the case here, as well -- if you've got a strong parental support network -- they work with the child with the device, they talk to the child when the child has problems, because they're going to have difficulties at school, at home, or with the device, or whatever -- you're going to see better outcomes in this situation than if you end up asking, you know than if you end up dealing with parents who have very little interest in their children, don't take an interest in their lives, things along those lines.

I mean, it's been kind of interesting watching some of these parents and children interact and kind of talking about their device, you know, kind of leading each other and going "Okay" -- you know, it's amazing how much the parents know about what's going on in their children's lives, so far, of the children we've assessed. I don't want to use the word "looking forward to," because that's a bad way of looking at it, but it would be interesting to kind of see some of these parents, perhaps, that aren't quite as involved. How are these devices working in these situations where the parents aren't involved? Because, although the device may work fine, part of the function is quality of life. And the parents are going to be very interactive in that aspect of the device.

And, of course, then children have to deal with school setting and maturity of peers and things like that. I mean, if they're around very immature peers who are making fun of them all the time, their quality of life may not be quite as enjoyable as in a situation where they're with more mature people who are understand their disability or their issues or whatever the case may be.

The other thing, too, with looking at environment for children and adults is, children still require care. And this was kind of mentioned before, as to what's the burden of caregivers and things like that. So, basically, this is going to be based on their needs for their disability or whatever the case may be. So, they could have additional care in addition to what they need for their disability.

Children also have less control of their lives and environment than adults. And I think this is very clear if we look at something like attention deficit hyperactivity disorder. It's more prevalent in children than it is in adults. I doubt if it's because there's any difficulty with hyperactivity or things like that. I doubt there's differences there. I think part of what's going on is, adults can control our environment. Most of you here have been pretty good throughout this whole presentation and throughout all the presentations, sitting here, paying attention, you haven't danced on the table, you haven't run around the room, things like that. I would expect the people who would have those problems sitting still are -- probably don't have the same professions that we do. They're probably out doing more things. You know, they have more control of their lives. They have a very different career path than those of us who have to sit at meetings for exorbitant numbers of hours.

So, that's the thing. Children don't have that. You're stuck in the classroom for 7, 8, 9 hours a day, whether you want to be there or not. We, on the other hand, have control. At least some control.

And also, too, the problem is that the peers of children are less mature than those of adults. So, you know, we don't see somebody who looks a bit abnormal, and start pointing and laughing at them. Kids do that. That can be a big issue for some of these children.

So, we've heard it before, we're going to hear it again, and I'm sure we're going to hear it again and again and again: Children are not little adults. And I hope I've given you some demonstrations of that here. There are unique issues that arise when we assess these children. Most importantly, we've got to deal with their development, and we have to realize that different factors affect their quality of life. They deal with multiple settings, and the importance of their support system cannot be over-emphasized.

And that's all I have to say. And I made if on time.

[Applause.]

DR. PENA: Thank you, John.

Any questions for Dr. Chelonis, John?

Yes, Dr. Pearl?

DR. PEARL: Very enjoyable perspectives. Thank you.

DR. CHELONIS: Yeah, two standing ovations of the meeting, at least, I think.

[Laughter.]

DR. PEARL: Yeah. But, another fact that occurred to me while you were talking about how people respond to the environment, context, past experience: Some of these devices are high maintenance, some are almost zero maintenance, others have intermittent maintenance. And we haven't really talked about that, but the way people respond to their environment made me think about this. For example, the one of the beautiful things about the shunts or the vagus nerve stimulator is, you can virtually ignore it forever; of course, you could ignore it, to a detriment, and have a malfunction or a problem, and then not realize there's a problem. You may have to respond in a crisis mentality. And then, some of them, such as the vagus nerve stimulator, gives the person the opportunity to exercise it and utilize the magnet to stimulate it in the event of a seizure, to try to abort the seizure, as opposed to just prophylactic. So, there's this other side of these devices, which is how much maintenance and how much control the patient or the family has, in terms of their use.

DR. CHELONIS: Yeah. I mean, thinking about that, too, to some extent, you know, let's say you've got to spend 2 hours getting ready, because of your device, in the morning. All of the sudden, there goes spontaneity that comes with youth. You know, somebody calls you up and says, "Okay, I want to go to the movie," well, you're going to miss that show. You got to wait to go to the later one, because it's going to take you an hour and a half to 2 hours to get everything organized or adjusted. So, I mean, that's certainly one of the issues there.

And you're right, like shunts or things like that, where people don't see them or they don't require a lot of maintenance or care, you may have better issues with regard to psychological quality of life than you may have with things you have to adjust or work with more. And that may be something to think about, from the regulation perspective, is making these things easier to deal with on a daily basis.

DR. PENA: Dr. Marks?

DR. MARKS: I guess I should mention, I have no nothing to disclose. I guess I should have done that up front. But, I have nothing to disclose.

You know, one bias that I have not really heard discussed is the issue of selection bias. And I have to admit, I was originally thinking of it in terms of the study and who would participate. And so, you have an automatic selection bias when you start. But, it actually goes well beyond that, because there's a selection bias, at least for some of the devices, about who gets a device.

Now, for a shunt, there's a lot less selection device, because it's a lifesaving device. But, for other of these devices, there is some selection bias, because if you have a family that can't manage the device, you're much less likely to offer it to them or to the child. And which device you offer depends on how compliant you think they're going to be with therapy and things like that. So, we haven't really accounted for that yet.

DR. PENA: Thank you.

Other questions or comments? Response?

[No response.]

DR. PENA: Thank you, John.

[Applause.]

DR. PENA: So, I think the next segment of the agenda had us having an open panel discussion. And I know that we are competing with lunchtime. So, I thought we could probably have a an abbreviated discussion of if we go back to those first two questions that Kristen had presented: What are the best approaches for enhancing the protection and promotion of public health in children and adolescents for the neuroprostheses? And the second question, What are the unique needs associated with currently marketed neuroprostheses for children and adolescents? We try to address the second question first, with some general comments from around the panel. And then, we moved the first question to the afternoon session, because I think that'll fold in nicely with some of the presentations that we have lined up in the afternoon.

So, to start just the discussions I know we're going to be breaking soon, but to start the discussions, you know, it's -- I think a lot of the presentations focused on growth and development, surgical considerations, and human factors. And I was pleased to see that, in, you know, for example, Dodie's presentation, you had identified longevity, malfunction, infection. These are other considerations that I think cut across different device types. And I was hoping to see what other perspectives are, with regard to those crosscutting considerations, that would be helpful to discuss in this forum. I'll open the discussion up.

DR. JALLO: Yes. What Dodie brought up is very important. I think, you know, when we implant a shunt in an adult, for example let's say they're 60 years old we know that shunt just needs to work for a few number of years before that person, you know, succumbs to old age. In children, the longevity is very important. As an example, you know, any device that we implant in children, we really want it to last the lifetime of that child or adolescent. But, we know that's not going to happen, regardless, whether it be a VP shunt, a -- the VNS stimulator, Baclofen pump, or any of the devices available us today.

And I think the biggest concern is, one, the generator. How long will that generator last? It's battery-operated. You know, there is technology trying to work on rechargeable batteries and all, but that's not available. And I think that's very important for children, because every time you need to replace the generator or a piece of tubing, it's a surgical procedure, and there are associated risks with that. Infection is one, and two is scar tissue. As -- you know, you -- every time you operate, scar tissue forms. It makes it more difficult for future implantation or for future revisions of those devices. So, I think that's extremely important for any of these neuroprostheses is longevity of the implant.

DR. PENA: Dr. Friedman?

DR. FRIEDMAN: Yeah. One of the things that I think is a ongoing issue with the devices and somebody mentioned earlier about when it comes to medication, it's pretty easy just to stop a medicine and sort of assess a response to it. One of the problems that I think we face in clinical practice all the time is really knowing when a device is malfunctioning, and the pains we go through to trying to make sure that that device is really malfunctioning before you are willing to take it out, replace it, whatever it is that needs to be done.

And again, I'm not sure how much emphasis is ever placed on this would come into the post-marketing of it but, really we -- good at reporting events and reporting complications, but we're not really very good at identifying the complication. And, by that, I mean, How do we differentiate when the shunt truly is working, verse not working? You know, sometimes you've got to go and stick a needle into the shunt to measure the pressure. Sometimes you've got to do an external pressure monitoring over a 24-hour period. All of these introduce the critical question of risk, because now you have to face a possibility of infections being introduced.

And I think the need to develop sort of smarter devices is really key. We're starting to see some of that technology develop in spinal cord, for example, where they now have sensors that can actually measure the pressure of the one bone, the one vertebrae on the other vertebrae. And you can really use external monitoring to monitor those forces. And I believe others here may speak better to this that with the VP shunts they're starting to develop pressure-sensitive monitors that can be interrogated externally. And I think these sorts of things are really big issues. And it's a very clear distinction, when you're dealing with a device, compared to when you're dealing with a medical product.

DR. PENA: Dr. Peckham?

DR. PECKHAM: I had a few comments that I'll make this afternoon. But, I just in taking a shot at some of those questions that Kristen presented to us, I identified six things. So, let me I'll just read them off, now. And I think a lot of them have actually been discussed this morning.

Size, weight, positioning of implantable components are, you know, certainly different, in our experience. The form of the technology I had here something like, "encircling nerves and growing diameters of nerves," and I went to try to do a search, and I was unsuccessful, but at least I'd like to try to bring it up for discussion. So, you know, sort of encircling nerves, and maybe it's a -- you know, the size issue. Lead management, especially with growth but, I think it actually might be a non-issue from the literature that I was able to look through, but external components, you know, usage environment, minimization of componentry, you know, sort of and, you know, especially trying to eliminate the use of external components as much as possible, or wires and that sort of thing.

Then, with regard to children, the replacement sort of the backward-forward compatibility and replacement all of the surgical management issues and what happen when technology changes and, you know, you have some components that are old and maybe some components that are new and, you know, a zillion things associated with that.

And certainly, you know, the imaging I think this came up, you know, this morning, and I think it will come up, you know, time and time again. But, you know, particularly with regard to MRI and, you know, brain imaging but, imaging throughout and the issues with regard to having being able to get good images is going to be important, throughout a lifetime.

DR. PENA: Thank you.

Dr. Tilton, and then Dr. Waltzman.

DR. TILTON: As I was thinking about this, and the fact that's been made that these children, who often have multiple disabilities and issues, may have more than one of our neuroprostheses, one thing that has come to mind is, like with the shunt dysfunction, suddenly the intrathecal Baclofen pumps work differently, as well. And so, this sort of inter- you know, not reliability, as much but, so much the interaction between these different things are very important, too, because it can look like a shunt dysfunction I mean, it can look more like a pump dysfunction, because spasticity is coming up, and actually it's dilutional effect from a shunt. And so, you have to remember that these things are very much, you know, related.

DR. WALTZMAN: I think when it comes to cochlear implants, the issues are just a little bit different. Certainly the size of the device, particularly externally, is a factor. Internally, the manufacturers have done a very good job in making it thinner and smaller, so it's appropriate for children and adults. Externally, they've also made, I think, some very good strides, in terms of making it smaller. I think some of the more unique issues of the pediatric and adolescent population, when it comes to cochlear implantation, is the postsurgical care. It's very different in for children and adolescents than it would be for an adult. You have to take a lot of care the parents, if the child is very young, need to take into consideration what mode of communication they want for their child, be it manual, total, or oral. And then it behooves us to plan for that child appropriately, depending on what the desires of the families are and what the needs of the child will be. And you have to follow that through for quite a long time.

I think that efficacy here, versus effectiveness, is a very big deal when it comes to implantation. What I'm not clear on is, Is this the role of the FDA to really examine this? And how are you going to do it, from a long-term standpoint? I think your comment was very to the mark, is that your job is to bring something to market safely and with efficacy. The efficacy of cochlear implants, technically, from the labeling and manufacturer's standpoint, is, Can a child hear? Does it give them some amount of hearing? What they do with that hearing and all those other issues, I don't know who where that falls under and who it falls under. We need to look at that, as providers of the service. We need to deal with that. And, I think, more and more we certainly are, especially when the kids are becoming adolescents. Then it's really who have had these implants for 10, 15 years, and now we need to deal with those issues. And indeed, I think the larger implant centers are trying to.

But, I think the issues for these children are, indeed, very different than just putting in a device that certainly is efficacious it's safe, for the most part, and it's efficacious. But, the effectiveness of it depends on a lot of other issues that we also need to plan for and deal with.

DR. PENA: Dr. Friedman, Dr. Pearl, and then Dr. Marks.

DR. FRIEDMAN: You know, I appreciate the comments, earlier, about the FDA's role in, obviously, regulating the devices. And I think this really, maybe, speaks to the heart of it, because is really is a concern, or problem, as to where that level of regulation does come in. I think relatively recently the FDA was looking at I think it was called Duraseal, which is, you know, the device used for sealing off the dura after intercranial surgery, and they were bringing forward it for use in intraspinal surgery. And again, it showed that at the time, interoperatively, it was very effective, but at 6 months down the road, the leak rate was exactly the same whether or not you have a device implanted. So or whether you had the Duraseal used excuse me. And so, it seems to me that there is some element of regulation that must take place, in terms of ultimate outcome, in that, yeah, it did its job at the time of surgery, but if you know that device is going to fail 6 months down the road, should you be approving it? Because once it's approved, it's going to get used. And unfortunately, there isn't a compelling need or demand to follow, postmarketing, other than adverse events, what happens to these devices.

And I agree, I it's not clear to me where that level of regulation does come in.

DR. PENA: Thank you, Dr. Friedman.

Dr. Pearl?

DR. PEARL: Well, to address the question, just very briefly, just some summative areas of emphasis that we've already talked about I and others are these: longevity it's been emphasized, it's a key factor -- I the suggestion of needing a smarter device, that is really important, because we need more information from the devices, instead of going to these great lengths and efforts to figure out what's going on with an individual patient who may have a malfunction.

The technological advance problem is not problem, but it is, because these require replacements, or replacements are necessary, and one has to account for those.

Imaging is an issue. I hadn't really heard too much about it until those recent comments, but that is an issue.

But, I have to say, the overriding issue, I think, is the one that was brought up from the cochlear implant expert, of which I'm not, which is efficacy versus effectiveness. And I think that really gets at the next question: best approach. I just want to volunteer, my response to that is that the FDA clearly has to do the job of evaluating efficacy to get these on the market. But, I think the FDA also has a responsibility to address effectiveness. I don't know that effectiveness should be a barrier to approval, but I think it has to be addressed with approval.

DR. PENA: Thank you.

Dr. Marks, Debra Nussbaum, and I think Malvina will get the last words for the session.

DR. MARKS: Thank you. For the last 3 years, at Cook Children's, we've actually hosted a pediatric DBS task force, where we've invited groups down who were involved in significant numbers of pediatric DBS cases. By "significant," that probably means 10 or 12 or more, because nobody's doing huge numbers yet.

We have actually been wrestling with some of these issues now for about 3 years, trying to come up with some answers. And a number of issues have come up. One regards patient selection: How do you choose who's an effective patient? And this really does go into, How do you protect the children? Because, for some of these devices, there's no effective screening test. For intrathecal Baclofen, you can do a screening trial and at least know that it will do what you want it to do, or you get an effect that you are not satisfied with, and this is not a good idea. But, for DBS, and probably for cochlear implants, I understand there is no effective way to screen somebody. You simply have to say, "They don't respond to other things. This would make sense, with what they have." And you're forced to go forward with a surgical procedure, really without knowing, with any reliability, what the outcome is going to be. And the families have to be fully informed of that.

Thus, the importance of doing a couple of things. One is clearly having some type of comprehensive team approach to these children, so it's not the decisions are not resting with one physician or one team member. But, you really need a very comprehensive approach to how you're approaching these children, which also brings forth the need, then, for centers that really specialize in children's care and have some and have developed some level of expertise in that. Not to say that adult centers can't do some of this, but they certainly need to have some protections in place for children that are undergoing these procedures.

Pre- and postprocedure, then, you also have the issue of accessibility. Children come from long ways away to get some of these devices done. For intrathecal Baclofen, our radius is probably 6, hours for people coming in for refills. So, this is where industry has actually been very helpful. And by extending battery life and extending reservoir sizes, you know, you can cut these visits from 6 weeks to 6 months. And that's huge, in terms of caretaker burden, back to that same issue again.

But, for DBS, it's even more complicated, is there are less as there are not yet many places doing children, we're seeing children from across the United States that are coming. And now you're kind of managing them long-term, in that, you know, they come in once or twice a year by plane to see you, instead of the usual way. And so, I think, you know, advancing some other ways of caring for them, and even advancing telemedicine across State borders, would be helpful, so that we can have ways to work with local providers and yet provide them with the expertise of what needs to happen.

And again, I just I really think that there is a great role for institutional review boards to review the procedures and things that have been put into place to protect the children, even for devices that have an approval, even if it's a HDE approval.

DR. PENA: Debra Nussbaum?

DR. NUSSBAUM: Just two quick comments, one about these are specifically related to cochlear implants, but maybe it does generalize. With the malfunctioning of the device so tied into communication and with young children you know, right now, we're seeing in the beginning, they said, "Oh, the failure rate was really low." But, as more children are getting implanted, we're seeing more and more. And the kids can't really communicate. Sometimes it's a hard failure and it just stops working. But, when these kids have what they're calling "soft failures," it's sometimes a very slow process of the light kind of dimming and the child not being able to hear. And it's not always clear cut. And I think that's something unique that we need to look at in this population of young children.

Another issue that just has come up in I mean, not just come up, but back in 2003, when they were looking at implants possibly being related to causing meningitis and the FDA's, you know, really looked closely at that. And there are immunizations that are required. And it'll be interesting and important to look at followup care related to that. I haven't heard much, now that they're doing more of the immunizations. But, what are the outcomes, now that they are required? Is it still a possibility that it is associated? And I think it's important that we look at that, as well.

DR. PENA: Thank you.

Dr. Eydelman?

DR. EYDELMAN: Considering my comments are going to keep you away from lunch, I'll keep them very short.

Just wanted to clarify that some of the postmarket studies that we require are actually mandatory; i.e., they become a condition of approval. So, while we can sometimes put something on the market, in the case of a pediatric device, if we think that we it's that while 2-year data is sufficient to get reasonable assurance to get to the market, it's very common that we would ask the sponsor to follow up with these patients, or a new cohort of patients, for an additional 5, 6, 7 years, however many years that we feel is necessary to get the true feel of the utility of the device, long term.

And I agree with everything I heard, in that FDA's role is not very limited. And, to that end, we are here to listen, and hopefully improve our total product lifecycle of these devices.

Lunch.

DR. PENA: So, thank you.

I'd like to thank the panel members for the morning discussions.

We will begin promptly at 1:30 for our open public hearing segment.

Lunch is on your own, for attendees of these workshop. And there is food availability outside the conference room, for public attendees, as well as there is local shops and restaurants.

And I would close this session until this afternoon. Thanks.

Panel members, if they can just stay here for a quick note.

[Recess at 12:40 p.m.]

A F T E R N O O N S E S S I O N

-- OPEN PUBLIC HEARING --

[1:40 p.m.]

DR. PENA: Okay. Welcome back, everybody.

Next segment of the agenda includes the open public hearing segments of the agenda.

I just have a couple housekeeping items:

Both the Food and Drug Administration and the public believe in a transparent process for information-gathering. To ensure such transparency at this workshop's open public hearing session, FDA believes that it is important to understand the context of an individual's presentation. And for this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement, to advise the workshop participants of any financial relationship that you may have with any firm or any group, their products, and, if known, the direct competitors that is likely to be impacted by the topic you address in your presentation.

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

Likewise, FDA encourages you, at the beginning of your statement, to advise workshop participants if you do not have any such financial relationships.

If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

So, we have two presentations signed up for the open public hearing segment. Our first presenter is Dr. Angus Wilfong, associate professor of pediatrics neurology at Baylor College of Medicine. He is also medical director of the Comprehensive Epilepsy Program at Texas Children's Hospital in Texas Houston, Texas.

Dr. Wilfong?

COMMENTS BY ANGUS WILFONG, ASSOCIATE PROFESSOR OF PEDIATRICS NEUROLOGY, BAYLOR COLLEGE OF MEDICINE

DR. WILFONG: Good afternoon.

Is this microphone on?

I would like to thank the panel and Dr. Pena for allowing me this opportunity to share with you my personal experience with using --

As Dr. Pena mentioned, I work at Baylor College of Medicine. And for my disclosure, I would like to say that I've received research grant from the NIH and from the pharmaceutical and medical device industry. I also served as a consultant to several pharmaceutical companies and am a consultant to Cyberonics, the manufacturer of the stimulator I will be speaking about today, and they have sponsored my travel to this meeting to share my experience with you today.

I devoted my life and my career to helping families help their children live with devastating neurological diseases; in particular, epilepsy.

I've been practicing at Texas Children's Hospital for the last 10 years, and this is the largest children's hospital in North America.

As a clinician, I see patients I see a lot of patients with epilepsy. I see patients every day. I see 50 to 60 children with epilepsy each week, and most of these children have medical epilepsy.

Before being in Texas, I was in Wisconsin, and I practiced at the Children's Hospital in Wisconsin and the Medical College of Wisconsin. I started the epilepsy program there for 5 years before moving to Texas.

I published extensively on the diagnosis and treatment of childhood epilepsy and am an active participant in a number of our professional organizations, including the American Epilepsy Society, Epilepsy Foundation, America International League Against Epilepsy, Child Neurology Society, and the American Academy of Neurology.

I have personally prescribed the vagus nerve stimulator in children, over 400 times, in children ranging from 6 months of age to 18 years of age. The therapy is a critical component to the comprehensive care and management of children with refractory epilepsy intractable epilepsy.

When children are referred to our epilepsy center, we perform a careful characterization of their child's seizures to identify their epilepsy syndrome. As you know, there are over 30 different types of seizures, and dozens of different epilepsy syndromes then begin with medical treatment using an antiepileptic drug. Unfortunately, medications don't always work, and we can only completely control seizures, in children with epilepsy, 60 to 70 percent of the time. So, that means that 30 to 40 percent of children and adults are going to continue to have seizures despite our best treatment, our best medicine.

These people are referred to as having medical refractory medically intractable or treatment-resistant epilepsy. For these individuals, we perform a thorough reevaluation to reconfirm their specific syndromic diagnosis and, at the same time, determine if they're candidates for a second for resective epilepsy surgery. Brain surgery is always our first choice in management of intractable epilepsy offers a chance and hope for completely stopping the seizures. Unfortunately, most children with refractory epilepsy do not have a surgically remediable epilepsy syndrome. They have multiple-onset seizures, and we just can't do epilepsy surgery. These children have a grim future that affects ongoing uncontrolled seizures, combined with high doses of antiepilepsy medicine, which the children require, have devastating effects that can be catastrophic. Seizures don't make you smart, and high doses of antiepileptic drugs don't make you smart, either. So, these children aren't able to get the education that is so necessary in our society today.

And if you don't have a proper education even if you're not having intermittent interruptions of your consciousness and body control with seizures, what can you really do in our society today to maintain a job and have independence and fulfill worthwhile life experiences?

The children also suffer from serious psychosocial consequences of their disease, both from the effects of the seizures and the drugs on limiting their independence, especially, as it was mentioned earlier this morning, the exciting times and challenges of adolescence. But, they also suffer terrible stigma, fear, and ignorance of our population in general. And epilepsy continues to have a terribly negative stigma in our society today.

Uncontrolled epilepsy is also a potentially life-threatening disease. People with uncontrolled seizures are at daily risk of accidental death, and drowning remains one of the commonest causes of death in epilepsy, of people getting careless.

But, they also could have SUDEP, or Sudden Unexplained Death in Epilepsy, and that remains a big challenge to as to whether to share with our families that their child could suddenly die unexpectedly from SUDEP. We still don't really understand what SUDEP is or what causes it. But, it's obviously catastrophic when it occurs.

So, it is absolutely critical that doctors have the ability to use all necessary tools that are available to get the seizures under control as best as possible and as soon as possible.

For patients with intractable epilepsy, research studies have shown that even a modest reduction in overall seizure burden, as long as that's not at the expense of untoward adverse effects, can have a significant improvement in the quality of life.

In my experience, VNS therapy does improve the quality of life. We believe it is safe. We believe it is well tolerated. And we believe it really helps many children with intractable epilepsy. It works at least as well as adding another drug. But, what is unique about VNS therapy is that its efficacy is maintained and sustained over time. It doesn't have that honeymoon effect that we're so familiar with, when we add another drug to a patient with epilepsy, only to have a transient benefit, but the seizures return in weeks, or a month or two. That is not something we see with VNS therapy.

Every day in our clinics at Texas Children's Hospital, we see the beneficial effects on the quality of life of our patients, and this is reflected in our high reimplantation rate, upon battery depletion, which is in excess of 85 percent.

In addition, as was mentioned earlier, the magnetic application of the generator can have a big impact on the quality of life. This allows patients or families or caregivers to give an on-demand additional dose of stimulation that, in many children, can shorten, or even completely stop, a seizure.

Only a week ago, I received a call from a mother of one of my tragically multiply-handicapped children, and she was in tears. And my nurse was concerned something was really wrong and she transferred the call to me. I happened to be in the clinic and I said, "What's happening?" And I was concerned that Jackson was back in the emergency room with another prolonged series of seizures, and intubated again. That had happened over and over again in his life. And she wasn't in tears of fear or upset. She was in tears of happiness because he had recently finished his ramping up of his stimulator, and he started to have a seizure and, for the very first time in Jackson's life, the mother was able to stop the seizure by simply swiping a magnet. And she called to share this with us because it had such a huge impact. And even if Jackson's seizure burden stays the same, if he has a seizure a day or a seizure a week, but instead of going to the emergency room when an episode of epilepsy, the seizure lasts a few seconds, which he stops with the magnet -- statistically, he's a nonresponder in the traditional randomized, controlled study, but for this family, and from my perspective on quality of life, this is a major reward.

The only other alternative families have at the moment for stopping seizures at home is rectal diazepam or Diastat. And you recognize when children get bigger and stronger and more independent, the use of Diastat becomes socially impracticable -- practically difficult.

So, in summary, once we establish a diagnosis of epilepsy, we begin with medications. But, for the 30 to 40 percent of children that aren't going to respond to drug therapy, we do a thoughtful evaluation to see if we can do brain surgery. And if we can't, we recommend vagus nerve stimulation.

I would like to encourage the FDA to consider all available data on therapies that could benefit children suffering from catastrophic neurological diseases like epilepsy, and consider expanding labeling, not just based upon on randomized controlled clinical trials.

Thank you.

DR. PENA: Thank you, Dr. Wilfong.

Are there

[Applause.]

DR. PENA: Are there any questions for Dr. Wilfong from the panel? Audience?

[No response.]

DR. PENA: Thank you.

Our next speaker is Dr. Laurene McKillop, from the Hydrocephalus Association. At the Hydrocephalus Association, she is chief executive officer.

Dr. McKillop?

COMMENTS BY LAURENE McKILLOP,

CHIEF EXECUTIVE OFFICER, HYDROCEPHALUS ASSOCIATION

DR. MCKILLOP: Thank you.

The Hydrocephalus Association accepts sponsorships from a variety of organizations, include some of them in -- but, I'm not here because of any of them, and they didn't pay for my way. In fact, I paid for myself anyway, because I'm chief executive of the Hydrocephalus Association.

The goals of the Hydrocephalus Association are to eliminate chance of hydrocephalus by stimulating research and providing support, education, and advocacy for individuals, families, and professionals dealing with hydrocephalus.

It is estimated close to a million people are living with hydrocephalus, average 6,000 babies a year, and thousands more diagnosed later in childhood. Hydrocephalus can strike anyone at any time, and its consequences can be devastating, ranging from repeated hospitalizations, infection, behavioral, physical, and cognitive impairments, and death. Treatment options are few. The best one, by far, is shunting. And yet, shunting causes -- and yet, since the first shunt was developed, in the '50s, there has been a -- and you saw the picture, a while ago, of the futile attempt to save his son. Currently, one in every three shunts fails in the first year after implementation. This failure rate is among the highest of all implanted medical devices.

Shunt placement remains the most common cause of brain surgery in children. After the first year, approximately 4.5 percent of shunts fail each year thereafter. The total cost to of shunt surgery exceeds $2 billion a year, excluding the cost of any relocation or accommodation. And these costs don't even begin to touch the cost of the burden of the disease on the people living with hydrocephalus, or their families.

While shunting has transformed hydrocephalus, in many cases, from a death sentence to a chronic condition, the need for shunt available shunts and available treatment is -- as shunt systems have changed little, relative to the other estimated technologies, and have caused many problems in living with hydrocephalus.

Shunt complications assume a major amount of a surgeon's time, are hugely expensive, and perhaps most costly, in terms of the hydrocephalus sufferer's quality of life, costs that are virtually not measurable across society. Investing in shunt improvements and treatments for hydrocephalus ought to be a priority, but, sadly, it's not.

To date, the investment by the Federal Government in hydrocephalus falls far short of the investment made in conditions that create similar or smaller public burdens. Surely we can do better.

On my staff, we have a person, age 22, who recently endured her 91st brain surgery. She was at work 3 days later. By the way, she wants only to live a normal, productive life. Without better shunt technology or better treatments, her desire is unlikely to be met. Don't we deserve more?

Thank you.

[Applause.]

DR. PENA: Thank you, Dr. McKillop.

Any questions for Dr. McKillop by the panel? By the audience?

[No response.]

DR. PENA: Okay. Thank you.

Our next segment on the agenda actually, let me just ask the any other audience attendees if there would be any request to make a statement before the panel.

Sure. If you can give your name, affiliation, and

COMMENTS BY TOM PENNELL, TRANSONIC SYSTEMS

MR. PENNELL: I'm Tom Pennell, with Transonic Systems. We're a biomedical company in Ithaca, New York.

We're currently in a Phase II NIH grant, developing a flow sensor to be used in hydrocephalus. We're have two versions of the sensor. One is used on an extraventricular drain. And the long-term goal for the sensor is to be implanted and to be able to communicate with the sensor transcutaneously.

We've sort of run into an odd thing, where all the parents and families that we run into are very responsive, and they're thrilled that there's new development going on in the area of hydrocephalus. And then, when it comes time for signing up for a trial with a device, it's sort of a "not my child" mentality. I was just curious if anybody would comment on that.

DR. PENA: Thank you.

Comments from the panel? Suggestions on enrollment?

DR. ROBINSON: Do can you talk a little bit about the risks that they would face? I mean, is this surgically implanted, or is it just a bedside

MR. PENNELL: The device, as it is right now there are two versions of the device. Right now, we're -- you're doing clinical trials. It's a low-risk device. It's basically put inline with an extraventricular drain. And we measure flow over a 24-hour period. And it seems like there's quite a few patients who just -- it's "I love the idea that you're doing it, but I really don't want to sign my child up for it."

The implantable device, yeah, it would be a surgically implanted device. Right now, we're just working with animal studies, and validating the technology. And at some point, we're going to be working in a clinical trial setting, and it's -- I think it's going to be difficult, in terms of getting patient enrollment.

DR. ROBINSON: Good. Just to respond to that, there are pediatric there are some children's hospitals that have clinical research units, which mostly do drug trials. But -- so, we'll have a kid that's getting IV antibiotics for a shunt infection. And the clinical research nurse approaches him about whether they can have one dose to test the pharmacokinetics of a new medication or something. And they're very agreeable to that in that environment. And so, it may be that if you approach things through the well-developed structure because part of using those research nurses is that they're not directly connected to the clinical team, and they know the culture and they have that comfort level.

We have very similar things if we try to roll out something in the NICU. If the NICU nurses that work there all the time and do the research do it, it goes much better than somebody else coming in from the outside. So, that may be an option. Because, from how you describe it, most families, I would think, would actually go for that if you have the surgeon's approval, which you have to have, obviously.

MR. PENNELL: Right. It's the surgeon that's approaching the patient for us.

DR. ROBINSON: And it may work better to have the research nurse do it.

MR. PENNELL: Okay.

DR. ROBINSON: That's just an option.

DR. PENA: Thank you.

Dr. Pearl?

DR. PEARL: This brings up a related question I have, probably for Dr. Robinson, And that has to do with the compatibility between different kinds of shunts. And what I mean by that and it touches on the question for example, the programmable valves I've seen, in my experience, different neurosurgeons having very different approaches and attitudes toward valves that are programmable or not programmable. And some say, for example, that they don't have the technology to work with a programmable valve, or they won't work with it, or they don't like them. And I imagine this is a problem, in the adoption of new technology. Can you comment on this?

DR. ROBINSON: Well, we, I guess, in pediatric neurosurgery, are similar to other things, that maybe change is not always good. But, there is quite there's an amazing amount of variability into what actual shunt hardware we use. And there's numerous studies that show it really doesn't matter, in terms of outcomes. The new valves have not been shown to be better. And there's actually some limited data that suggests that they may malfunction more. They some of the programmable valves cost two to three times as much. And if they don't work better, they don't have a lower incidence of revision, then there are some that argue that we shouldn't use them. Then there's others that so we have a problem of chronic headaches in some of our shunted children, and there are some that argue that maybe it will address those.

So, there's a there certainly is not enough data. There are well-done studies that show that no valve is better than another. And so and there also are several studies that show that you will have a lower complication rate, a lower revision rate, if you do things the same way every time. And that actually has great gained some traction, in that it doesn't matter if you put the shunt in the front or the shunt in occipitally. But, if you do it the same way most of the time, then you actually have a lower complication rate. And so, that probably is the basis of it. I don't see it being resolved anytime soon.

I personally don't think that the new the advanced valve designs are the answer to decreasing our overall problem with shunts. I think we need to move on to a new technology, such as artificial or biological arachnoid granulations or something. I mean, we just need to move on, beyond shunts. But, that's down the road.

DR. PEARL: Thank you.

DR. PENA: Thank you.

Dr. Friedman?

DR. FRIEDMAN: I think, just a comment about the recruitment issue for drugs that well, any study, whether it be drug or device studies. I think it's very, very much dependent on, as was mentioned, who does the recruiting. And we found, for example, with many of our studies, that when fellows or residents first approach patients to get recruitment for studies, our success rate was very, very little. Whereas, when people are really intricately involved with the study and they spent some time with the family and actually went through it, the refusal rate was pretty low. It was almost zero. And I would suspect that maybe, perhaps, this is more I don't know the specifics circumstance, but it may be more of an educational issue than anything else, I would think.

DR. PENA: Dr. Chelonis?

DR. CHELONIS: Well, I've done quite a bit of research over the years, and I've served on IRBs as well. So, with regard to the medical issues, with regard to the study I'm not familiar with your study, but if it's a situation where the patient actually has to do something above what they're doing medically like, for example, if you have to get this valve put in, you know, or have a shunt in, or whatever the case may be, they might be less likely to do it if it involves a new procedure, something they have to do in addition to what they're already doing. But, if you're in their for another medical reason to begin with, then you might be more likely to get some kind of compliance.

So, really I think it's one of the things that you know, how much of a cost is it going to be to the subject, not only with regard to risk, but also with time and other inconveniences, as well? So, if there's any way to, you know, combine it with another treatment or another medical another appointment or something like that, you might have better luck getting people in, as well.

DR. PENA: Okay. Thank you.

Why don't we move to the next presentation? We have, the next speaker -- welcome to the podium -- Lauri Rush, who will be providing a patient perspective for this workshop.

PRESENTATION BY LAURI RUSH, PATIENT REPRESENTATIVE

DR. RUSH: Hi. Good afternoon.

I want to start by saying I have no conflict of interest, no disclosures, other than the fact that I'm using this forum as an excuse to show cute pictures of my daughter. That's my disclosure for the day, so -- and, unfortunately, those of you are here as professionals, and not parents, don't have that luxury. So, I am at an advantage in this event.

My daughter's in the middle, here. This is when she was younger. I think it's actually before she had her cochlear implant. She was reading at a young age. And so, as one of the speakers just talked about, education is very important. We're actually very blessed, because she's a bright little girl, and has overcome a lot of difficulties in life to be quite successful now.

The other reason I chose to show a lot of pictures today is because I think that the patients and the families need to be given a face. And we get involved, in the medical profession, of what the best treatment is, and our research, and we lose fact of the we lose sight of the fact that we're dealing with people, with families. And I'm sure many of you have children. And if you've been faced with a medical problem with your child, then it takes on a whole new meaning, the work that we do. And so, I want to thank you all for giving me a voice today, and as well as the program. The research that you're doing with asking children directly about their experience, I think is extremely valuable. So.

I like the children to be defined as who they are, and not by their equipment. So.

People used to call kids with cochlear implants "CI kids," and I said, "You know what? My child is not defined by her equipment, she is a child. She has a personality and an individuality that I want to be respected."

I have a different experience than a lot of families that have deaf children. I actually have deafness in my family. Her deafness is genetic. My grandparents were deaf. My grandmother lived with us and helped raise us. I have my parents are deaf educators educators of deaf children. And I am a clinical psychologist at Gallaudet, and was in practice for a good 20 years before I had a deaf child. So, it was a bit of a surprise. All my immediate family are hearing. My nieces and nephews are hearing. So, it was a surprise, but it wasn't a completely unpleasant one for me, because I already signed and I had quite a benefit in that way.

I actually ran support groups for parents of children who were deaf. So, I always describe my journey as, I went to the other side of the couch. And that's been a humbling and eye-opening experience for me.

I also ran support groups for people who had adults who had cochlear implants. So, again, it's been quite an educational experience for me.

And, as a result, I also sign fluently. So, in making a decision about a cochlear implant, I took a whole 'nother view on how things could work for my child.

We talked about, with the cochairs of the presentation today, that I don't only bring the experience of having a child with a cochlear implant, but my daughter was born with other medical problems, as well. So, I've kind of had a fuller picture of the whole thing. Serena was born with a diaphragmatic hernia 50-percent survival rate. It took me a while to find out that that was the rate, because we protect parents, and we don't always tell them everything. And that's not helpful. And so, I can deal with things if I know what they are. The nurses on the NICU would always say, "Well, you you know, you act as if she's going to be fine and there's nothing wrong." And I said, "No. I know there's a 50-percent survival rate. I know her chances are even less because she was premature," and so on. But, having that knowledge, then I can put that aside and work towards making sure she gets the best care she can.

So, I think it's empowering to parents and families to give them the information. And it's hard it's very difficult to get information. When she was in the NICU, it was hard to find out what the survival rates were or what the complications were. Even today, what are the long-term impacts of her diaphragmatic hernia and her surgery? That's they're are still difficult for me to get information on.

She was at Children's National Medical Center for 4 months, on a ventilator most of that time. I spent at least 12 hours a day with her, working part-time, going to the hospital, back and forth. And I, again, think that one of the problems we have is, we don't empower our parents enough with making them a part of the team. At that point, I knew my daughter better than any other medical professionals on the unit. And when her color changed, I knew immediately there was something wrong with the equipment or her breathing or something else. And trying to get people to understand that was difficult. I just think what -- we need to give more credibility to the parents and the families that are with their children every day.

She was on oxygen for a year, a feeding tube for 8 months. And she when she was discharged from the hospital, she had normal hearing, through a ABR test. So.

While at Children's, she had stopped breathing several times CPR, broken ribs, an overdose of antibiotics, pneumonia, surgery. We just missed "ecno" by hair. And thank God for that. And she turned out, coming home and had a lot of care after she got home, but she was fine.

So, I've not only had the deafness and the cochlear implant, but we've had other medical devices to deal with, as well. And there is something just about having your child on a medical device that, when you go out in public, whether it's a hearing aid or a oxygen tank, people look at the child as with pity, and look at the child as a patient instead of a child. And I think, as a mother, that's excuse me one of the things that bothered me, I think, the most about when she become deaf is, here we go again with some more medical equipment, where people are going to look at the equipment instead of my child. So.

The picture here is actually a friend of my daughter's who drew his self-portrait. I have a similar picture by my daughter, but I couldn't find it. So. You might see that he has a cochlear implant on one side and a hearing aid on the other. My daughter drew the same type of picture of herself. I think, over time, the devices become a part of who they are. And it's just sort of secondary nature. They're not ashamed of them. It's not an issue, it's just part of who they are and how they function.

She actually probably started losing her hearing about a year, because of all the complications she had with other medical problems. It wasn't identified right away by me. Usually it's the parent that figures it out before the professional. In my case, it was the physical therapist who said, "I think she's not hearing you." She had about five spoken words. But, because I work at Gallaudet, and signing is fun for hearing kids, we I was signing to her. So, she kept picking up sign language, but not spoken words. And so, eventually we went in for testing, and she was diagnosed identified I use the word "identified" as profoundly deaf, and got hearing aids put in immediately, and we started in the Gallaudet's pre- -- parent-infant program. And she got services very quickly. Again, we are very blessed, because I have access to information that many parents don't have. So.

At the time, when she had her ABR and was identified as deaf, they told me she was not a candidate for a cochlear implant. For me, it was amazingly, some of you will think somewhat of a relief, because I didn't have to make that decision. And then, later, I think -- through our audiologist at Gallaudet, I found out that, indeed, she was a cochlear implant candidate. We put off the surgery, because of her lung development, because of the diaphragmatic hernia; the pulmonologist didn't feel she was prepared to go through another surgery. So, that delayed it somewhat, which actually was nice for me. It gave me time to research everything I could possibly read on the device and on the surgery and et cetera, et cetera. So.

Again, making the decision was very hard for me because, as a member of the deaf community and having deaf family members and deaf colleagues, I knew that she could be perfectly successful and have the quality of life that I have, without being able to hear. Sure, there would be more challenges with regard to access and so on. But, I knew that she would be fine. So, to -- for me, it was an elective surgery. And that was a really difficult decision to make, especially after her medical condition to begin with. So, we had just kind of gotten stabilized, and here I was, having to make the decision again about surgery.

And I know you all asked me to cover a little bit about the deaf community's reaction. Things have changed over the years around cochlear implants. We see cochlear implants all over Gallaudet now. The we have a upper a topnotch administrator who's getting ready to go through a cochlear implant. So, it's become quite accepted. There are still a few people who don't support it and feel it's a cultural issue and a slap to deaf people to say, "You're not good enough." But, I think for the me, the deaf community was very supportive. I said, "I'm not taking something away from her. I'm simply giving her something. My daughter's first language is sign language. She's a -- very much a part of the deaf community, and I haven't taken that away from her." She describes herself as half deaf and half hearing. And she's perfectly comfortable in that role. So.

Preparing for surgery took a long time, a lot of information. Again, it was very hard to get information about research that was not marketing information. That was very frustrating for me. I wanted to know, for example, death rates you know, facial paralysis rates. And so, I had to call the companies to get this information, and they'd say, "It's very low." Well, what does "very low" mean to you? That's your definition of "very low" when it's your child is different than my definition. So, you know, do I want to take that risk? And I want the actual information. I asked the surgeon, "Can I see a videotape of the surgery?" And they said, "Oh, we don't encourage parents to watch that." Well, guess what? I have a right. I want to watch it. I want to know what she's going to go through. And you don't need to protect me. I'm an adult. I can make decisions based on, you know, my own intelligence and my own maternal instincts, on whether or not I want to do this. But --

And I do understand that many parents would get upset by this and decide not to go through the surgery. But, isn't it best to know? I never did see the videotape, by the way. So.

She went through surgery. Again, listening to the parents was very valuable. My I knew my daughter's medical history. I knew her pulmonology issues. I told the anesthesiologist, "I suspect we're going to have trouble, when she comes off the anesthesia, getting her off the oxygen. He pooh-poohed me, said she'd be fine. Guess what? She had trouble coming off the oxygen. So, I think that it's again, it's just really important to involve the parents in the preparation and the planning.

She did have some complications. They again, everybody tells you the surgery is outpatient, it's really easy. They kids recover very quickly. She didn't recover quickly. She was in the emergency room 2 days later with an infection. It took her a long time to get back on track. So. But, she did. She's fine. And the she was activated a month later, which is pretty typical, and immediately took to the device. She had already been wearing hearing aids since she had had some hearing for some time, for several months. I think it was easier for her to get used to that. And we went through a lot of speech therapy and training, through different programs in our county, and so on, to make it all work.

One of the questions that I was asked when we were preparing for surgery was which device to choose. How the heck do I know? I'm a psychologist. I don't know anything about medical devices. And the surgeons are expecting parents to make this decision. But, again, what data do we have to make that decision? Only thing I have is the marketing data from the different companies. And so, I would urge you all to do more research and provide that research to parents, so that they have more data that's perhaps not as biased and not used for marketing purposes. So.

Some of the things that we've had to think about related to using her device at home. Put my I have to use my own devices here excuse me. I first want to say, the cochlear implant is absolutely an amazing device. And I'm going to tell you all the limits of it, which is why I'm starting with that, because we took a child who could hear no speech, per se, to a child who can now hear 70 percent of speech. And having said that, I want to say, it really -- it changed what her life is. I mean, she now she's trying to decide between being a medical doctor and being a Broadway star in Annie and Mary Poppins. So, this would not have been something that would have been in our definition of possibilities without a cochlear implant. So, I do want to commend people for coming up with this device and making it available to our children.

However, I do want to say, the kids are not hearing. They're hard of hearing, at best. If I said to you, "I'm going to put your kid in a school, and they're only going to hear 70 percent of what's said and that's in a one-on-one, quiet environment," is that good enough for you? You know, probably not. Well, guess what? You put them in a classroom with other noisy kids, and it goes down 50 percent. So, that's not going to do it for my child.

So, the you know, there are a lot of limits of the device. And they don't make the kids hearing. So, to take sign language away from my child was not even a consideration for me.

The times that she cannot hear when you think of the day-to-day environment, what's a quiet one-to-one environment, that's rare in a child's life. So, you get, you know, environments I made my little list of the times that she can't hear me well. In the mall, in the car, on a airplane, in the bath, upstairs, watching TV, when other kids are talking, in a classroom, on the soccer field, in gymnastics, in Sunday school, in the theater, in the movie theater, swimming, playground, riding a bike, when the dishwasher's running, when there's music playing, in the middle of the night when she doesn't have her device on, first thing in the morning when she doesn't have her device on, at this workshop -- she would not be able to hear the speakers at this workshop without a sign language interpreter. So, the other examples: in the classroom, the intercom announcements at the airport. I'm interpreting all day, when we go to the airport, on, "What are they saying?" because I've created a child who won't tolerate not knowing. So, she has full access, because she has sign language and she wants to know, "What are they saying when they make the birthday announcements in the morning and at school?" She wants to know which kid's birthday it is. So, I've, fortunately, created a communication monster here. So -- those are the limits of the device.

There's a lot of additional technology that's available. There's a lack of training for parents on how to use that technology. There's FM systems, there's direct connections to different devices that are very helpful. But, again, it's hard to get the schools and the parents educated to use those.

Equipment failures are so much higher than I ever expected, both internal and external devices. We went through about a year with an external device that wasn't working properly. And they kept, over and over I mean, we've changed we changed it out, and so on. But, you know, the question was always, Well, is this part of her attention problem? Is this part of and it was always, "blame the child" instead of, "look at the device." And I think this happens more often than not with kids with cochlear implants. They're always looking to see, Why is the child not benefiting? and not looking at the equipment. And I'd like to see that reversed, where we look at the equipment first and rule that out before we look at the child, because I know a lot of other families who have had device failures where this is a problem.

Again, my communication choice my child is bilingual, bicultural. She's as fluent in ASL as she is in spoken English. She uses both, back and forth, depending on the situation. She's able to fully participate in activities where there's -- at times, she has an interpreter or somebody who signs for her. After-school program is a good example. We've gotten them to hire people who can sign, because when the announcements are made, she can't hear. When it's a noisy environment, she can't hear. So.

She loves to be involved in a lot of different activities. One of the problems with the device is, How do you keep it on when the kids are in gymnastics? You know, you've got the helmet issue. Again so, she goes to gymnastics. There's a sign language interpreter. She can't hear anyway. The gym's noisy. So, she can fully participate.

There are also financial issues involved with the parent what parents have to consider batteries, things that are not covered by insurance. Even the ongoing insurance to keep the equipment working is, you know, $1500 a year, and so on and so forth. So, always fighting with insurance companies to see what they'll cover.

The one thing I never thought about, as a professional, was childcare issues. Huge. And I'm thinking, cochlear implant's nothing compared to shunts and other things that you all are talking about today. Trying to find a babysitter, a nanny, somebody who's willing to take care of oxygen, who's willing to take care a cochlear implant, who's willing to sign when needed, is virtually impossible. If you think about your own kids and the childcare challenges you have for them, and you add in a medical problem, it's huge. It's a real one of the biggest challenges that I never considered, as a professional.

The school considerations this was my biggest concern, when I found out she was deaf, because I know there's no perfect option. I've worked in schools for the deaf, I've worked in mainstream environments. I knew that there was no perfect option. And that remains, today. We have a very good option. She actually attended Gallaudet's Kendall Elementary School for the first til first through first grade, where it was both signing and a spoken language environment. She's now fully mainstreamed at Montgomery County, which is we're in Montgomery County, right? Silver Spring area in a classroom with two other deaf children who have cochlear implants, an interpreter, an a FM system. She's above grade level. She actually started pre-K early because she was doing so well. So, she's doing great, but every year there's a new challenge. This year, we realized, "Oop, the teacher's starting small group discussions." We have one interpreter, three deaf kids, and one FM system. How's this going to work? So, every year, there's a new challenge that we have to take on and we have to advocate for. And I have to teach her how to advocate for herself, because sooner or later she's going to have to take that role on, as well.

The teachers are not trained on how to deal with the equipment. They don't she had to go to three different places last year to get her batteries changed on her FM because they wouldn't let her do it. And so how much class did she miss just trying to get a battery changed for her FM system?

So, these are constant problems for parents. So, when you say, "Parents don't want to participate in studies" well, gosh, who has the time and energy to do that after you're advocating for your kid all day?

We're very blessed with the classmates. They have the school she's in has 25 deaf kids. The PTA has sign language classes after school. The kids love to learn to sign. So, she's very well accepted and integrated into the program there, and has numerous hearing friends and deaf friends.

The developmental challenges that you all talked about, as well, are going to be coming, and, I know, for some of her friends, have already come, where, when they get hit the adolescent ages, and suddenly the playground activities change to more of who's dating who and the gossip and this involving speech and language and so on it's going to be harder for her. And it is harder for kids at that point, where they feel ostracized if they're different, and so on.

Some of this I've have already talked to. I think it's critical that the parents are empowered and that there's not a condescending attitude towards them when they try to express their opinion to the medical professionals. I think they should be a team member of equal value when making medical decisions, and so on.

Again, I think we need to look at ruling out equipment problems before we look at, Is there a child problem? One of the nurses on the NICU, when I was there, talked about parents, or mothers in particular, having a invisible antenna into what's happening with their kids. And I think that is very accurate and very true. It's like, I can look at my child without anybody else saying it, or without her saying anything, and know she's understanding a conversation, just by the look on her face, whereas somebody else assumes she's understanding and even the audiologist who I work with assumes she "Oh, she can hear us." And I say, "No. She has no idea what you said." And then she'll we'll ask her, and she doesn't know. So, I think, again, you need to include the parents and the children, themselves, in making the decisions about what's happening.

I think -- again, I think time is lost if you're not looking at the child and the parent to get information.

The coordination-of-care issue we have audiologists all over this city that are involved in our care. And it makes it really complicated. We have a different audiologist who takes care of her hearing aid, because we have Kaiser insurance. So, Kaiser does the testing. They pay another private insurance company to provide the hearing aid. We get our cochlear implant at Johns Hopkins. The school has a audiologist. We have all these people providing treatment, and there's no coordination of care. And trying to make sure that everybody has the same information and that we're all in the same page on trying to figure out what's going on with her is a challenge. And it was a challenge, also, when she had the medical condition, when she had the diaphragmatic hernia, trying to get the eating specialist to communicate with the pulmonologist to communicate with the pediatrician, and so on. And I felt like I was the case manager, and I wanted to just be the parent. So, I would encourage you all, in the medical profession, to think about that.

Again, I would just encourage more research and information be available to parents. That is you know, having the training I had as a clinical psychologist, I can actually read some of the things and understand some of it, not necessarily all of it or even close to all of it, but I wonder about parents that don't have as much training in that area, that can actually look at statistics and try to figure things out. We need to make the information to parents more friendly, more accessible, and have it be research that comes from the medical professionals and not necessarily marketing.

One of the things that recently I looked at was the bilateral cochlear implant issue. And, fortunately, she has enough hearing in one ear to benefit very well from a hearing aid, so I didn't really have to consider it. But, everything I found was all marketed by the cochlear implant companies, which thank you, that they are doing this work and, you know, researching this; I do appreciate that but, they market it in a different way, that makes you look at it differently. And when I really sat down and looked at the information, I realized that the benefit was not going to be great for her. So.

And finally, thinking about the future, I would love to see more technology be available to her. I want to know more about the long-term impacts of cochlear implants. Of course, some of that we won't know until this these kids move up. I do know that working at Gallaudet -- for example, this year we had a new signer's program for students who don't already know how to sign when they come to Gallaudet. And we had 50 students -- this was a huge group for us -- that came in without signing. Over half of them have cochlear implants. Okay. So, these kids are ending up at Gallaudet, which, again, tells me the device is not the final answer. I mean, it's helping these kids, but they're not feeling included, or they're not feeling like communication is smooth. So, we need to continue to make it work better for them, and give them both. I mean, we teach our hearing kids to be bilingual. Why can't our deaf kids be bilingual? We all think it's cool to teach little hearing kids to sign, but then, all of a sudden, somebody's quoted some research that's that is, oh, that deaf kids won't learn to speak if you sign to them. Well, that's just not accurate. And so, why can't these kids have both? Why can't they have it all?

I would like to see smaller devices what you spoke about, smarter devices, that tell us when something's going wrong. The FM system is very difficult to use. When you put it on, you have to reset it to take it off, and so on. I'd like to see that be easier to use. And finally, looking just the effectiveness overall, as we move into the future, in making the device more effective.

Pretty much that describes my experience as a parent, and what I'd like to see happen. So, I thank you for your time.

[Applause.]

DR. PENA: Thank you, Ms. Rush.

Any questions for Ms. Rush?

Yes. Dodie?

DR. ROBINSON: I just have a quick question. When you were doing your research because there are some limitations in what's written did you talk to any parents of kids that had cochlear implants? I mean, I'm sure you did. And how did that compare with your other research?

DR. RUSH: I probably got my most valuable information from other parents, and still do. Gallaudet Debbie Nussbaum will talk more about what they do at Gallaudet but, they have parent panels on a regular basis. And she and other staff people put me in touch with a lot of different people who had cochlear implants. So, I talked with adults who had cochlear implants, parents, and so on. And I still get a lot of help from other parents. We compare, you know, "How do you keep the device on? What do you do? Which system do you work best with?" So, some of the most valuable research came from parents. It did that answer your question? or, you had a okay.

DR. PENA: Dr. Marks?

DR. MARKS: Yeah. Very nice presentation, and very helpful. I know we spend a lot of time pre-educating parents on -- particularly with DBS, but I know the cochlear implant team does the same thing. And actually, we give videos to everybody and insist that parents watch it first, and then make their own decision about whether the child should see it. And we do link our parents together. They're just invaluable as a network. And some have decided yes, based on talking to other parents, and some have decided no.

But, the other thing that you've mentioned that I really thought was interesting is, I really didn't know the effectiveness of cochlear implants. And so, as you look when you start looking at the data from this "ask the children" study, you know, it becomes a is-your-cup-half-full-or-half-empty type of study. Is a 50-percent improvement in hearing is that good? Or is that even more frustrating than not having hearing to start with? And I don't know the answer. I don't have a cochlear implant, so I don't know the answer. But, you know, if you look at the overall effectiveness of all of these devices so, you've got cochlear implants, that are 50 to maybe 70 percent effective, but roughly 50 percent. You've got DNS, which is, you know, a third effective at reducing seizures, kind of like any other seizure medicine. You've got DBS, which ranges from 20- to 80-percent improvement in motor scores, depending on the disability that you're looking at. It'll be kind of intriguing to see how people interpret those levels of improvement. And I guess it probably depends a lot on where you're coming from and what your perspective is as to, "Am I better off than I was before?"

DR. RUSH: And I have to say, I feel -- as I started out with, I think the device is fabulous, and I think we are far better off with the device. And she can appreciate music and she can talk to hearing friends. And I hope someday she can talk on the phone; she can't yet. So, I do think it's a wonderful device. It's far better off. I think the danger is that people think -- they hear her talk, and she has excellent speech, and they forget that she can't hear in many situations. And so, the -- I think the danger is that we're not educating parents and professionals and teachers on the limits. And so, they think that the child can hear anything, and the child is actually missing 25 to 50 percent of what's being said.

DR. PENA: Dr. Waltzman?

DR. WALTZMAN: I think that cochlear implants, in this particular group, differ from some of the other devices that we're speaking about, in that they are much more labor-intensive in many ways, and particularly for the pediatric and adolescent population. Every cochlear implant center works differently, and every group of children -- and adults, as well -- have different expectations. And depending on patient demographics, the expectations can be different from child to child, from adult to adult. So, there are a lot of factors here that come into play. And I really do think that it behooves the implant centers to offer this kind of service that you talk about, where it needs to be coordinated. And for these children and adults, as well it's not just kids the adults need the same kind of intensive care there and I believe, at many of the larger implant centers and I think Hopkins has that, as well, now, being one of the larger implant centers is that, at the end of the evaluation, you sit down with the family, you explain somebody at the implant center goes through all of the available devices, the pros and cons, so to speak. And then the family makes a decision, based on the information that they've been given by the implant center and by the staff at the implant center. It is a complicated process. There's no question about it.

And it doesn't stop. The complication doesn't get less after implantation. As a matter of fact, it gets more complicated. There's the programming issues. There are the educational issues. And as the child gets older, that confounds the complication, as we're learning very rapidly.

But, I think that we you did speak to other parents, and that's certainly the right way to go. I the I don't know if the New York a New York population is generally a tougher group, I think. And so, what we faced, lots of times, is, they are on the Internet, and they come in with preconceived notions of things, like you said, that you get more marketing material. And we have to kind of stop that. We have to you have to channel that a little bit. While the companies do an amazing job of giving out information, it's not always relevant to a given individual. If you don't know the patient demographics, you don't really know what might be right for that particular patient.

So, we do instruct all of the companies, when they speak to somebody who is from our center, they have to contact us immediately and let us know what transpired. I don't know if this only one of the only medical devices where the patients or the families deal directly with the companies for information. This, to me, is very unusual. When we did a -- cochlear implants, we said, "Why are they talking to the companies? You know, why aren't they talking to us?" And it's just that maybe there is some lack of information.

Just to update you, there's a ton of information and research in the literature in the scientific literature -- on bilateral and on a lot of these other things, now. So, that, I think, is better.

And it's a tough situation, though, to coordinate everything. But, I do believe that it behooves the implant program to do it.

DR. RUSH. Right. Thank you.

DR. PENA: Dr. Chelonis?

DR. CHELONIS: I'd like to mention that you brought out a very good point, which I tried to mention in my talk, and I think it bears mentioning again, that these children are kind of caught somewhere in the middle. As you mentioned, you know, the cochlear implants has given your daughter new opportunities that she might not have otherwise had, which is a huge step up from not having those opportunities, and talks about, maybe, 20-, 30-, 40-percent success. But, at the same time, though, your daughter's still going to have some limitations; she can only hear 70 percent of things in a normal room, she'll have to have an interpreter, or things like that.

So, I just want to kind of call attention, from kind of a methodological point of view, the baseline you use to assess this or these devices or whatever -- is very important here. If you're assessing based on what she can now do that she couldn't do before, this is wonderful. If you assess it, though, based on the limitations she's going to have in the future, there's some room for improvement. So, I just want to kind of have you all mull that over a little bit.

DR. WALTZMAN: I think that this is a case where every child really is different. It's not necessarily 30-to 40-percent success. There are children who can function less well than she can. There are also children who function very, very well. I'm a lot of our kids are mainstreamed no interpreters in the room, and they get the highest grades in regular classrooms. So, I think the difficult thing with cochlear implants and with assessments, even for us, is that you're dealing with an incredible an incredibly diverse group here, where the results are incredibly diverse, so that your measuring tools are giving you one thing, but, in fact, everybody is functioning differently out there.

DR. RUSH: I just want to add to that, as a response, that when I asked Johns Hopkins, her audiologist there, "Could Serena function in a hearing classroom without an interpreter?" and she said, "Why would you do that?" And I said, "Well, you have other kids going out there without an interpreter." And she said, "Yeah, they can't sign, so they're going to miss the 20 percent the 10 percent whatever it is." For me, I want her to have as much close to 100 percent as possible. So -- and she's right, they don't sign. My next question to her was, "Why don't you tell the parents to sign?" So, why not give the child everything?

And I know parents are in denial about that and don't want to learn. And that's what I've had to deal with, in 20 years of working in this profession, even when there weren't cochlear implants. But, why not give the child all options? And the child that's doing well in a classroom and comes to this meeting isn't going to be able to hear. I couldn't hear, today, so what are they going to miss? So, when she works for FDA later and has to come the meeting, I want her to be able to participate fully. So --

And even her interpreter this year said I said, "Can Serena ever function without an interpreter in the classroom?" And she said, "Absolutely not." And I said, "Why not? These other kids do." And she said, "Because she's way too nosey." And I said, "You're right. You've got my kid down, just like that." She wants to know everything and has a right to.

DR. WALTZMAN: We have -- I must say that 90 percent of the parents of our children with cochlear implants do not know one sign.

DR. RUSH: Right.

DR. WALTZMAN: They don't. And the and they that's just their belief. That's just their focus. And it's their choice.

DR. RUSH: You're right. And it I think when those kids end up at Gallaudet again, like they did this year, with 30 of them who don't sign and have cochlear implants, I think that's what -- we're creating another lost generation of hard-of-hearing students. So.

My own opinion, as both a professional in the field and a parent.

DR. TILTON: I just wanted to add one thing. I think that this is sort of across all devices or medicines or whatever you want to say, that this whole issue of goal, and ultimately the goal attainment scale, where you identify the goal you want, is the only way to equalize part of this. But, if the person goes in to get a cochlear implant or pump or anything else, and they say something that's unrealistic, "I want to hear, 100 percent," you need to know that, walking in. You need to sort of identify what their goal is. And in order to say it's a success, if well, if I could hear, you know, half of the conversation it's a very different person who says, "I want 100 percent," because that person is going to be disappointed. And that can be the multiple people identifying goals. But, in -- sort of like the goal attainment scales, and some of these other ones, where they say, "My goal is to do X," then you say that person met their goal, or didn't meet their goal, and that equalizes it quite a bit.

DR. RUSH: And as long as the parents have accurate information, if they make that choice -- again, that's their decision. So.

DR. PENA: Okay. Thank you.

Why don't we move to our next presenter, Ms. Charleene Frazier, from the National Spinal Cord Injury Association and United Spinal Association.

PRESENTATION BY CHARLEENE FRAZIER,

NATIONAL SPINAL CORD INJURY ASSOCIATION AND

UNITED SPINAL ASSOCIATION

DR. FRAZIER: Good afternoon. Dr. Pena, on behalf of our association, I would like to thank you for inviting us to be a part of this very interesting and informative day. Thank you.

I have no conflicts.

I wanted to share, first of all, a few highlights about our association. We are a membership organization. We have 25- nearly 25,000 individual members who are living with spinal cord injury and/or disease. We also have hospital and business memberships. Our mission is to educate and empower people with spinal cord injury and disease to achieve the highest quality of life.

About a year and a half ago, we began collaboration with United Spinal Association, and we now offer a combined resource center, known as Spinal Cord Central. We do not provide medical advice or opinion.

Who do we serve? We serve people living with SCID, their families, their caregivers, their friends. We serve the healthcare professionals, especially those who are unfamiliar with spinal cord injury. We serve both a national and an international community. And we do provide language Spanish language assistance.

What do we do? Well, basically, we do a lot of compassionate listening. We hear from people either by phone or by email. We listen to them, try to provide hope to them at a time that for the people with a new spinal cord injury, where there's such a life-changing event. So, we do a lot of listening.

We also do a lot of teaching and educating. After we learn what their need is, we do provide them with resources and information. Quite often, it's trying to help them find local resources that they can immediately access.

But, the I think the most important thing that we do is -- when people have been thrust into this life-changing event -- is that we want to help them learn to be their own best self-care advocate, and provide the tools to help them do that.

Our Spinal Cord Central has its own Web site, and our association also has its own Web site. Both Web sites contain a tremendous amount of information for the consumer, with fact sheets, knowledge books, and a lot of other information. We also, on our NSCIA Web site, keep a posting of studies that are being done, so that the consumer has a way access this information.

Before I get into commenting about the questions that we were asked on the ASK CHILDREN Study, I do want to say that our comments today are not based on hard data, but on years of a lot of collective listening to the consumer. We've also talked with a master's-prepared public health nurse who works with home assessments in vulnerable populations, a master's-prepared school nurse with 25 years of experience, a retired teacher who worked in the special-needs population, and a spinal cord injury physical therapist who does independent consulting. And I we did I we did respond to the two big questions. So, I will go ahead and share with you what our thoughts are on this.

First, in protection and promotion of public health, we believe that assessment is really important. We believe this is an opportunity for the public health nurse to assess a family to determine if they're going to be a family that can support the need to be consistent, dependable, and responsible in the use of the designated device.

The other important question that we see so much: Is there adequate funding to support this family to use the device in the way that it's designed?

The second important area is evaluation. When families contact us about -- whether it's new equipment, new devices, or a clinical trial that they want to participate in, we urge them to seek the and find -- the initial costs, the ongoing costs, and the time commitments. What is expected of this family to participate in a responsible way?

And then, thirdly, education and advocacy. You will hear, throughout all of my comments, that education and advocacy are one of the areas that we just really believe is important. So, certainly for parents and the children that are considering a device an implantable device -- it's important that they know that this device may not be an option for all people or for all injury levels.

And when people come to us, quite often what they're looking for is a cure for spinal cord injury. So, it's really important that they understand that muscles below the level of injury can respond to electrical stimulation, but that is not going to cure the spinal cord injury. So, it's really important that that family have a realistic understanding of what is possibly being offered to them.

They need to know that it will require surgical intervention. And they also need to know that they should have access to a doctor with the expertise that can monitor and manage the medical side of the device. And most certainly, we would encourage that parents and the child be engaged in the care of whatever the device is that is being presented to them.

We also believe it's important that the professionals the nonmedical professionals that are going to interface with this family and with the child -- be informed about the what the resources are that are available. And I'll speak to that in the next section. But, how can we reach out to school nurses and to teachers, to coaches that are working with these children, to, maybe, make them aware that there's a resource available that they have not had suggested to them?

The unmet needs that we thought about: One of the things that we're so aware of is, How do you reach consumers? And I've heard, today, comments about parents researching on the Internet. We're very aware that there's a lot of people that don't have Internet access, and will never have Internet access. And in today's world, that's a real liability.

The other thing is, we're here in the Washington, D.C., area. We hear from consumers from all over the United States all corners. And believe me, there's some extremely rural areas. So, people that have the unique needs that we're talking about today are very limited in finding the resources.

I heard someone talk about children coming by plane to be managed. And I would agree that the era of telemedicine is probably the more that can develop or, the more technology can develop, it will benefit the people that are in these remote areas.

We also heard people talking about how important the information that parents need to have. And I think when people come to us, they don't know what questions to ask. And I think the suggestion of a panel of the medical personnel that talk to the parents and educate the parents so they know how to make a wise decision for their child is so important. So, we need to help them know what questions to ask.

Financial considerations is a big issue. We hear from people, so often, that their insurance denies coverage for a piece of equipment because the insurance company believes that it is either experimental or research. And many times it isn't. But, it means that this family has to appeal a denial. And we do know that research shows that 70 percent of people that have a denial for insurance do not appeal. When they do appeal a denial, they end up, in over 50 percent of the time, those denials are reversed. It takes a lot of hard work. And you're talking about a family living with spinal cord injury and some of the other conditions we've heard today. It takes a lot of time on that person's part. And I think that's just it's a real tragedy, in today's world, because it's tough. It can be done, but it's tough.

We would certainly support a culture of safety, where there's continued research to identify guidelines and best practices for pediatric neurotechnology. We do know, for instance, the diaphragm pacing system, the spinal cord stimulators, are labeled you know, that they are not do not have safe and effective effectiveness for pediatric use. And yet, they need to be used and do make a difference in quality of life.

We were also asked to comment on home considerations. And again, I can't stress enough the importance of education education of the parents, others in the home that are going to be interfacing with the child, the caregivers, and certainly the child needs there needs to be an identified plan so that that child can gradually assume responsibility for his own care and for the care of the device that's going to be implanted, if that's the case.

What are the demands of the device? Well, we certainly know that a spinal cord stimulator we also know the vagus nerve stimulator are hybrid devices, where there's an implanted unit and there's a control unit. So, that's going to imply a lot of education education of the parents, the caregivers, and education of the child. And, as I said earlier, we certainly want that child to eventually assume their own responsibility for that.

And, depending on the needs of the device, it will dictate what needs to happen in the home, whether there needs to be what kind of adaptations and accommodations, how this relates to other members in the family. If there's other children, how does this affect them?

Schools considerations: Children that have physical disabilities should have an Individualized Education Plan, just as the child with a cognitive disability has. And that plan should identify goals and benchmarks for the child's physical well-being and how they're going to participate in the school setting. Those goals need to be determined by a both a formal and informal evaluation that's made up. The determination needs to be made by a team of teachers and therapists, case managers, nurses, certainly the parents and child.

Important questions to ask when the child's getting ready to go to school: How is his device going to affect his or her return to school? Can the child independently manage control? And, if not, who is going to be there to help with that? And what are the potential side effects that the that needs to be considered? What are the actions that need to be taken? So, a lot of education.

Need there needs to be education of the school personnel and of the population. And I think -- first of all, we heard earlier about how the children are going to react with their classmates. I think if a child is going to be compliant with a device, it's going to be important that their classmates be educated and be aware of how of what this child is coming to school with. So, it's going to be important to do sensitivity and awareness education in the classroom. Does the child need a classroom buddy? And, if so, who would that child be? Or, if it's a child, how's that child going to help?

And I just would cite a personal example. I have a 10-and-a-half-year-old granddaughter with a severe scoliosis. And I know it isn't an implanted device, but I think describes the sensitivity and awareness issue. She has a rare muscle disorder and has developed severe scoliosis and is now in a body brace. And when she was 9 and -- and this was part of her treatment -- she said to her mom, "Can you and I go to school and tell the kids that I'm going to be wearing this brace?" And so, that is what they did. And my daughter-in-law did a beautiful job. And in while she was talking to the class, she said to the children, "And here's what you can do to help Carlie." And, you know, it made a wonderful transition, so that Carlie has not felt different from the rest of the kids, wants to be involved as actively as she can.

So, it's I guess my point in that is that we need to suggest to parents creative ways that they can help their children be as normal as possible in that school setting. And I think that's going to affect that child's compliance.

The other important person is the school nurse or the school therapist. And that person is going to be the child's advocate in the school setting. And if that nurse has not received enough information about the device that's being used, she should or he should -- contact the medical clinic or the doctor who has prescribed the device and learn specifically what's involved, what she needs to observe for, and what she needs to know, so that that she can be an advocate for that child. And it's also important, I think, that we remember that not every district is going to have a school nurse at every school. So, who is going to be the person in that school that's oversees that child and his or her particular needs?

And last but not least, the classroom teacher, whose primary responsibility is academic instruction, but nevertheless has the responsibility to know when to call for help for that child that's in her classroom.

Optimization of devices: We were asked to comment on that. We can't stress enough, access access to the kind of care that is required. We deal with this all the time with people living with spinal cord injury who do not have physicians or healthcare people that truly understand the unique presentation of somebody living with spinal cord injury. So, it's our recommendation that people have access to a facility that is familiar with pediatric spinal cord injury, that's familiar with the neuro-devices that are being recommended. And kind of based on that last discussion that was occurring, there's a lot of talk within the pediatric American Association of Pediatrics to go to a medical whole model of care. I think it's so appropriate, with the kind of children that we're talking about today, because there's a whole team of people that need to be involved in the care of that child. And it needs to be coordinated instead of a lot of fractured pieces.

Secondly, with the device itself, I just would like to share another personal example. My coworker is a C3 C4/5 quadriplegic with a freehand system implanted. And two things that she's encountered: one is, she has a system that is now no longer being produced. So, where does she get the support, the tech support that she needs for this? And the technicians are not as expertise with it as they were when this was first implanted. One of the things that has worked for her when she has had some technical problems with that device is that she has an occupational therapist that she called in who worked with the technician in collaboration to fine-tune the control mechanism so she gets optimum hand function. So, I think that's something for us to think about. Who are the specialists out there on that team that can help the technician make whatever this device is work to its optimum for that individual? And for the individual to also have access to the OT and PT people for consultation when it's needed.

Certainly for optimization, the parents and the child need to have a device that's appropriately labeled, that the instructions are clear, that they understand the instructions. And I heard earlier, and would suggest also, the as we move towards technology that can offer more smart devices or barcodes anything that can reduce the risk for error and again, for the this family is to know what questions to ask, what observations to make, to know the possible side effects and the appropriate actions to take.

Medical treatment and medical care: And again, it's reemphasizing access to the people that have the expertise. That medical team, the pediatric spinal cord doctors if there's more and more, we're seeing people who are becoming achieving a subspecialty in spinal cord injury, and we really do encourage people to have access to that kind of care access to a pediatric physiatrist, OT and PT with spinal cord injury expertise.

And lastly and again, the importance of funding and reimbursement, not only for the equipment, but the supportive services that we heard Lauri talk about and the specialty care Does this family have access to those resources? And that all needs to be known up front before they make the decision that this that they're going to obligate themselves to a device.

So, in closing, I would like to say that I think our overall recommendations for the work that you're doing and that the study is trying to achieve is education, advocacy, reimbursement, and access to the right kind of medical care.

Thank you.

[Applause.]

DR. PENA: Thank you. Any questions for Ms. Frazier?

[No response.]

DR. PENA: Okay. The next speaker we have on the agenda is Ms. Debra Nussbaum, Cochlear Implant Education Center, the Clerc Center.

PRESENTATION BY DEBRA NUSSBAUM,

COCHLEAR IMPLANT EDUCATION CENTER, THE CLERC CENTER

DR. NUSSBAUM: Hello. I'm going to try to go into some more about education and advocacy. We've already had Lauri cover some of the information that I would be mentioning, as well as Susan Waltzman from NYU, who has also mentioned many of the things that I might talk about, as well. So, I'll try not to be redundant, but move forward so you guys can have a break.

I've been asked to speak on home and school considerations for children, pre- and post-cochlear implantation, because a lot of what surrounds the effectiveness of the cochlear implant is dependent on what happens before and after, as well as the surgery. The surgery is only one part of the picture.

Let me just say that, by training, I'm an audiologist. I've been at Gallaudet as a pediatric audiologist. And I've been there for over 34 years. I've had a chance to look at how deaf children have worked with traditional technology. And I will say that watching the outcomes of the children with cochlear implants has been quite a journey. I have to say, I was skeptical in the beginning. And I've seen the outcomes and I can see what the technology can do. But, I also see how much it needs to be a team. And that's the thing that I think we've heard repeatedly today. And I'm going to reinforce that, as well.

Some of the things that we talk about, in terms of advocacy Charleene, you were talking about with spinal cord injuries are similar to what I'm going to mention, as well, because I think, as well, when we have young children, what happens in the hospital is only one part of the picture. They go home to a family and they go to a school system. And if everyone's not on board, then you might as well just stop at the surgery. More so for cochlear implants. Some of the technologies we're talking about today you put the technology and the child does kind of off they go. But, with cochlear implant, from what I've seen, that is a little different.

In just going to talk a little bit about counseling families, their involvement in decisionmaking about which technology they're going to choose, what factors impact the outcomes that the families need to know about, and what some of the post-implant outcomes expectations are going to be. And then some considerations for maintaining this device lifelong, what habilitation is needed to actualize the outcomes, and what kind of educational environment best suits each child.

Some of the decisions families have to make for children with cochlear implants: Which hospital center are they going to even start getting the implant? From my experience and I've worked with families and educators from all over the United States some implant centers are very liberal, in terms of, they'll do a cochlear implant on anyone, pretty much, if they are an audiologic candidate. Others are very strict about, will they consider a cochlear implant for a child, for example, who is older and maybe isn't going to be as successful, in terms of actualizing full spoken language as their primary way of communication. Some hospital centers won't implant a child if they're using sign language. Some won't implant a child if they have other neurological disability. So, you really have to look and sometimes families do hospital shopping, in terms of which hospital will consider implanting their child.

Families have to make a decision whether they want unilateral or bilateral. There's a lot of decisions that some of the families have to make that other technologies implantable technologies they don't even have to think about. The hearing aid in the other ear, we in the beginning, children were told families were told not to use a hearing aid in the unimplanted ear. And as time has gone on, that recommendation has changed for the children who can benefit from a hearing aid in the unimplanted ear.

In addition, if the child isn't going to be implanted bineurally bilaterally at the get-go, keeping a hearing aid on that ear to keep that ear stimulated is often a recommendation, as well.

Which manufacturer? Many times, the families are told, "There's three cochlear implant manufacturers." But, there's not a lot of guidance as to which manufacturer might best meet their family needs. How many times does a child have to go in for any kind of surgery and you have to make that decision about which manufacturer you're going to pick of the device that's going to be implanted in your child? That's a hard one for families to make.

Families are told, "If you're going to benefit from the device, you have to have habilitation so that you're only going to use spoken language after implantation. And oftentimes the families are told, even before implantation, "Don't use any other kind of communication, because then your child won't actualize the benefit from the implant." Families are oftentimes fed differing information from differing professionals, which puts them in a difficult position.

If children if a child with a cochlear implant is going to be accepted into a school program, I do think it's really important that that school program, whether it's in the mainstream program, a school for the deaf, they be prepared to help the child actualize benefit, have the auditory training they need, the speech training they need, and look at where this technology fits in for each and every child.

And language and communication outcomes are different. You look at these kids in the top picture those are our babies those are our 11-month-olds. They're coming into our program hopefully, is we're looking at newborn screening. We're getting the kids in the program by the time they're 1 to 3 months old. And that's happening more and more. Then we can't get the implants on them maybe until 11 or 12 months, because of insurance and because that's what the FDA recommendation is. Well, what is going to happen to that child for that first 11 months of life? Putting those issues related to cochlear implantation might be different than the child, in the bottom picture, who is 13 years old came from another country, was adopted, had no language. Now, they're moved to the United States and they're getting a cochlear implant for the first time. They've had 13 years where they've heard nothing. And now we're putting in the technology. Does the technology work? Yes, we're talking about the efficacy of it. They can physically hear a pin drop. They can raise their hand for every one of those speech sounds. But, can they understand enough to learn? That's a whole different story.

And when you look at what the implant can do, when you look at the children who typically are being implanted, who have severe to profound sensory neural hearing loss and, of course, the candidacy has changed, and there's looking at all different types of hybrid technologies of acoustic and electrical stimulation at the same time, and different types of losses that may be able to benefit from an implant. But, this is typical.

And again, most of the kids can hear a pin drop and can raise their hand when I say, "Can you hear this?" However, we don't really listen with our ears. We really listen with our brain. And how the child is interpreting sound is the thing that we have to look at.

And success with an implant? That's a real vague term, because success, if you're only going to say, "It's understanding spoken language," is one thing. But, for some of these kids who are older and getting it, their quality of life may improve. They really enjoy their implant. They love it for music. But, can they understand spoken language for learning? Maybe 50 percent of the time. For some of the kids, hardly at all. But, who's going to make the decision on whether that implant is a success and whether you should consider that child for implantation?

So, you have to look at all these different factors when you're looking a whether the implant is going to be effective. You have to look at when the child became deaf. Did they use if they're older when they're getting the implant, have they been stimulated auditorally all this time, so that the pathways are open and ready?

The causes of deafness: Many of the causes of deafness also cause additional either learning disabilities, auditory processing problems. Some of these things are not going to be overcome by the implant itself. Whatever caused the deafness, the status of the cochlea might not be ready and able to take in all of the electrodes.

And again, back to age. In the beginning, when cochlear implants first were becoming more commonplace, the typical child that was being implanted higher high family involvement, higher socioeconomic groups. Now we're seeing kids with additional learning challenges, lower socioeconomic groups that might not have the supports in place to actualize benefit from the implant.

The child's learning style: Some children, whether they're hearing or they're deaf, some are more auditory learners and some are more visual learners. We have the kids who aren't risk-takers, in terms of their personality, and they're not even willing to try with the ear implant, and they're shy, and the outcomes might be different for that child, as well.

The family motivation to use the device, do the necessary training it's critical to the outcomes of this device. Having families understand that their child is still going to be deaf, have a realistic expectation about what this technology can do. It is a technology, and this group of children are going to be technology-dependent for the rest of their life. It's something the family has to understand what goes into that decision.

Language use in the home: We have more and more families who are, maybe, not speaking English in the home. We have culturally deaf families who have been using American sign language who are now choosing the implant. Suppose the family now the child's getting differing languages, one at home, one in school. Is that going to confuse the child? What language do you focus on? These are all things that we have to think about as post-implant. How are we going to address the needs of these children?

The device itself: Some of the children, all the electrodes cannot be implanted. Their outcomes might not be the same. Sometimes the families aren't even sure, don't -- they don't even know about that. I see it, on the audiologic report, that only half the electrodes could be implanted, but the family is still might have the expectations that all the electrodes were in place and that the expectations might be different. And if the family would know that, maybe they would tone down their expectations, in terms of what's realistic.

The map, which is the part after the child has the surgery, they have to go back for approximately 4 weeks to get the map, or the program, for the external part of the device that's worn. If you do not keep up with that map, then the surgery might as well be for naught, because you have to keep up, in terms of modifying it to be specific to that child and making sure it's adjusted on a regular basis.

For families who are going and moving far away now from their hospital implant center, that causes that's quite a challenge. And the manufacturers have are coming up with different ways the hospital implant centers -- in terms of, How do you get into the schools to meet the needs of the children? At the same time, I was talking with Susan Waltzman before, and she was mentioning how some of the challenges with that is, if you aren't doing the mapping while the parent is there, if you're doing it in the school, then the family doesn't have as much interaction with what's going on. They can't they don't understand the followup and they don't have as much accountability to the whole process. So, there are pros and cons of getting into the school to do the mapping that's necessary.

And again, I see kids most of the kids, I have to say, once they're implanted different than hearing aids a lot of times, in the past, the kids didn't want to keep their hearing aids on. Well, they really couldn't hear anything. With the implant, they are getting benefit from it, so they want it on most of the time. But, you do have some kids, especially in the beginning, trying to get them to keep the device on consistently, or some of the kids who are sign language users who might not use it all the time. You have to keep it on. You have to wear it consistently. It's a building process of learning. And if you take it off and then put it back on, then that's going to be a challenge, in terms of growing with the device.

And we talked about individuality today, but I say repeatedly, if you've seen one child with a cochlear implant, then you've seen one child with a cochlear implant. And again, I've worked with families for many years, and I do see the benefits of the technology, but I really do see the importance of having to counsel each family as to what it's going to mean for their child.

One of the things that we found helpful is this continuum of looking at the child, of where they come to when they're come to us when they're getting their implant. And the implant is an auditory technology, and we're looking at what it receptively can do. Child, maybe when they get their implant, at that minute in time, they're a visual communicator. The goal of the technology is to move the children across that continuum to becoming an auditory communicator.

Many families have that big A as the goal for their child. What we've seen, though, in reality, is, many of the kids with the implant fall more into somewhere in the middle. Either they still are a visual communicator and they get some benefit from the audition through the implant, and a growing proportion have the potential to become a mostly auditory communicator, but they still do need some visual supports to their learning. The proportion of kids who are becoming fully auditory communicators is still a smaller percentage than the kids who don't need some kind of visual support. I'm not saying that that's not going to improve with time, but it's not there quite yet.

Expressively also, we have kids who might understand a lot but, for whatever reasons, still have problems expressing themselves. So, we have kids I've seen I don't have any research on this, but a large group of kids, interestingly, who understand but have some sort of apraxia or inability motor planning to articulate what they want to say. I have one little boy who has Charge syndrome right now, and he understands quite a lot. In fact, he's doing a lot better, receptively, than we thought he was going to do. But, expressively, there's no expressive communication. So, there's been it's really been important for him to have some other means, whether it's sign language or it might be a communication board for this child to express himself. So, we have to look not only at kids' receptive skills, which is what the technology is built for, but how they are going to express themselves.

There's just in the spring, there was an article about looking at with the growth in the number of children with cochlear implants has emerged a population of children who are similar in the technology they are using, yet disparate in their demographic characteristics and spoken language communication outcomes. Again, which leads us to it's important to look beyond one single approach, in terms of education. And we want to look at linguistic and cognitive competence, and what that's going to mean for each child might be different. And oftentimes the path might be different for each child -- even if we're trying to help them become big A and big O communicators, sometimes that's going to it's going to look different from one child than another.

These issues are just more related to these children, again, being technology dependent for life, and who's going to pay for the internal upgrades of the equipment or the external a lot of times, the kids in our school some of them, once the equipment goes out of warranty, we really want the kids there are some insurance companies that will cover insurance, but I've spent a lot of time out in the pumpkin patch looking for external devices. We figured out ways to do it with -- you know, that fishing game where there's a magnet at the end. We've gone out in the field looking for the external device. With hearing aids we used to have the benefit of there would be feedback that squealing, we could hear it. I would stand out in the field, listening. Now we can't, so we have to figure out if this device is lost and it's out of warranty I've had some families who can't afford to purchase an upgraded device.

Then we have children who are wearing the internal device and nobody can afford to replace the external device. As we move out further and further, in terms of more and more kids getting the device, and they're getting older, that's I think we're going to see more and more of those kids, because not all of the families have the financial supports in place.

Cost of batteries and parts for life: The school we highly recommend that the school maintain parts and batteries. But, whose responsibility really is it? What is the school's responsibility, in terms of mapping? The IDEA says that it's not it's a medical device. It's not the school's responsibility. But, when you have a child that's sitting in front of you, you want to know that that child can hear you, if that's what that child is dependent on. So, we have to make sure the schools are involved in making sure that they're prepared to take these children.

Right now I'm working on a resource called a CI Tool Kit. A private firm is looking a research firm is developing a program for parents, teachers, and children, so that they can be educated about this technology that their peers are using. And hopefully that will help, in terms of some of the staff education for kids in the mainstream.

Habilitation: Right now it's -- there's a lot of controversy related to who is qualified to do the auditory and speech training. What credentials does that person need to have? I'm not going to go into the specifics today, but I think I'm not sure, in terms of how that needs to be regulated, in terms of who is credentialed. And what we have, even if we credential too strongly, is that there's not enough qualified people out there to do the training that we're recommending. And then the families are stuck, as well.

And who's paying for it? Sometimes the insurance companies are paying for the device, they're paying for the mapping, but not often the habilitation. And how much is that a part of the success or effectiveness of the device?

And then again, about some of the just the issues related to educational placement. Maybe full inclusion is the goal for many of these kids, that they should go to their neighborhood schools. I've had some of the families who don't necessarily want that to happen, because they lose some of the supports that they've had in a more self-contained, restricted environment, where a teacher is knowledgeable about how to best work with their child, or they have an IEP that helps guide what supports are in place. Sometimes, the children are, to their benefit, topping out of what supports are needed, and they don't need an IEP anymore. However, sometimes the families don't want that to happen, because they lose the support.

If the children are in the mainstream, like Lauri was talking about, it is helpful to be in a school where there's other children, families, teachers who have met a deaf child before. They understand that not everyone does the same with a cochlear implant. I've talked to other families who have a child in an included environment; the people have never seen the teachers have never seen another deaf child. They've never seen a child with a cochlear implant. And they've made an assumption, because maybe they saw it on TV, that this implant is now the child's going to be hearing; once they have this device physically on their body, that that's all that they need to account for.

On the opposite end, schools for the deaf, such as where I work, are sometimes seen as not the right place for kids with implants, because they're using sign language and the school for the deaf isn't going to look at the spoken component. And that's been one of the things that our program's really taking ownership of, is trying to work with other schools for the deaf, other programs that are inclusive of sign language, and showing, How can you make this environment the right place for a child with an implant and maybe even a better place for a child with an implant, for the early years especially, while we're trying to set early language foundations? Wait and see where that child moves from the V to the O and the S to V-to-the-A, the S-to-the-O continuum. So, that's something that is important, that we look at how each language fits in for the child.

Where does sign language fit in? Cued speech is another way to visually clarify English for a deaf child. Some families with cochlear implants are choosing to use cued speech as a strategy for their children with implants. When is an oral-only approach appropriate for a child? And suppose a child's moving from a sign language environment, getting their implant, moving across that continuum -- setting up some guidelines for when it is appropriate for them to transition.

So, with that, I've just moved through, very quickly, everything I've learned in 35 years. So, hopefully that that was helpful for you, and things to think about for kids with implants. And thank you for your time.

[Applause.]

DR. PENA: Any questions for Ms. Nussbaum?

[No response.]

DR. PENA: Okay. I we have a break scheduled for 15 minutes. I'd like to make a slight break, for 5 minutes, and then have everyone back here so that we can get started with the next presentation by Dr. Peckham. So, we'll take we'll reconvene at approximately 3:40.

[Recess.]

DR. PENA: Our next presenter is Dr. Peckham, from Cleveland Functional Electrical Stimulation Center, and he's been invited to give us a bit of a science perspective, research and development of neuroprostheses technologies.

Thanks.

PRESENTATION BY P. HUNTER PECKHAM,

CLEVELAND FUNCTIONAL ELECTRICAL STIMULATION CENTER

DR. PECKHAM: Thank you very much. It's been very actually, a very stimulating day for me. And in preparing this, I really had a chance to go back and talk with some of the people that I'd worked with during pediatric work, largely at the Shriners. So let me just make a couple of comments.

One of the things -- we were talking at lunch, and I know that -- you know, that after 3 o'clock the things don't stick that well. So, I'll try to -- you know, try to throw in a few things.

So, I'm a biomedical engineer. Okay? And I sit sort of at the intersection between technology development and clinical application. And Kristen, in our sort of little email conversation back, she said, you know, "You'll be okay if you stick to the sciencey stuff, right?" You know and so, I thought what might be interesting is to give you perspective about how our clinical research has really informed our directions for neuroprosthesis development. And so, in the things that I've put together, I really want to thank the people from Shriners Philadelphia who I've worked with a lot on the pediatric applications. And, specifically, M.J. Mulcahey has provided me with a lot of information.

So, just as a disclosure, I don't have conflicts.

So, here's what I'd like to go through.

And, you know, I forgot a -- to have a watch here. So, maybe you'd give me some 5-minute signal or something, Carlos.

The so, my experience with pediatric applications, what we've learned, and then some considerations for pediatric applications, and then maybe I'd throw in something that's a little bit self-serving, which is a sort of our concepts for future design. But, I think maybe it will sort of inform the way that we are thinking about multifunctional systems.

So, my experience in with pediatric applications largely comes in these areas from the Freehand system. Freehand system emanated out of our Case Western the FES Center. It was used in a number of patients at the Shrine, and I guess it really is an off-label use, but so, in pediatric patients. But, I think we've learned a lot from that, that might be helpful here. And they also use that in the lower extremity for some mobility applications. Then Vocare, which I think is in the list of your things, and what was learned.

So, here's just a the only quickie tutorial what the Freehand system is -- is a device that restores grasp and release in people with mid-cervical-level injury by electrically stimulating the paralyzed muscles in the forearm and hand to restore grasping function. And that consists of an internal unit and an external controller external coil, much like the cochlear device.

I guess it might be easier most of you are looking over here to point to this screen. Or, maybe not. Okay. I'll so Malvina, don't turn around. I'll do this one. Everybody else, look over on this screen now. Okay? So.

It used an external shoulder sensor as the control device. So, the person wiggled their arm forward and back and it controlled their grasp, basically.

And this shows what it's like on the inside with the device. And then a the leads going down the forearm, underneath the skin, to those targeted muscles that are used for the grasp.

So, now at the Shrine in Philadelphia, they were doing they did a number of subjects, in experimental protocol. And this is they, of course, found that this provided pinch and release and increases the level of independence. And it broadens the breadth of ADL. We were talking earlier this morning about all these different domains in which you have to measure. And when we did the clinical study, we actually did these domains, looking at impairment, functional limitation, and disabilities, and the impact on each of those. So, it increases spontaneity, improves functions and activities of daily living, and typically was the preferred method of achieving a function.

And here you can see this little I think she was an 8-year-old at the time. She subsequently passed away. I only learned this, this weekend, in talking to M.J. So, she was, you know, just a, you know, neat little neat kid, but, you know, showing here, with adaptive aids. And Shrine, of course, has a school within the hospital, as I'm sure many of you know. But, here using the Freehand to grasp. And so, there's a zillion slides that you can show like this. But, they're very impactful -- okay? using two hand to write versus one hand to write. In the previous one, you see she's using a splint to write versus using her hands. So, she can change objects and all those sort of things.

They were did a lot of work with adolescents. And what M.J. was telling me is that -- you know, how important this is for these teenage girls to put on their own makeup. And, of course, I've never been a teenage girl before, but I began to appreciate this, in working with some of those adolescents there. But, here's, you know, a girl putting on her makeup. So, you can see she had enough postural stability in her arm and hand to use you know, to do those kinds of things; two hands for holding, you know, better stability in writing. And so, the ability to do overhead reach, reach above your head was part of this.

And I think that bladder management for adolescents is so important. I mean, all of us went through adolescence, here in this room, except for me. And I think that -- but, if you remember those times of becoming much more conscious of your body then. So, the bladder management -- and individual bladder management is so important to these kids. And so, this guy is this young man is using his -- this Freehand system to catheterize himself, which is the way in which he provided the urinary control, to be able to do self-catheterization. Otherwise, you know, he either has to have an indwelling catheter or have somebody catheterize him, either one of which is not a very satisfying approach. And so, he could remove the catheter by himself, and all. So.

Now, they did Shriners did a number so, these are very impactful things. And I think that when we, as the designers of this technology, envisioned this, we did not think about "we did not think about" -- shame on us about this being used by children. Okay? So, I thought it might be, you know, sort of useful to give some reflections of what that means, and how that's impacted me. So, they -- in the Canadian occupational performance measures, there are a number of scores that were done a number of studies that were done. But, just as I just picked one. So, in doing different tasks so, you can see, in performance, there was an improvement over statistically significant improvement, versus however their best performance was in these different tests. There were a number of tests; it's too long to go into. And satisfaction so, their satisfaction with this technology was improved. But, I think that, as I'll show you in a second, this was not again, it was not designed to be used by children. And so, I'll you know, I think that with in the engineering field there's this principle of universal design. And I think that actually we could encourage the manufacturers or developers of this technology to think more about universal design as applied to these implanted technologies. And it's something we don't do now, that I'm aware of -- that we do at all. Victor, do you know of if that's applied in some of the any of this neuroprosthetic development or -- you know, we

DR. KRAUTHAMER: In prosthetics?

DR. PECKHAM: Yeah? In prosthetic but, in neuroprosthetic. No, I don't think so, at all.

Now, this device was also used in the lower extremity, and they did the comparison of these implanted neuroprostheses of -- the so-called Freehand the Freehand device with a knee-ankle-foot orthosis, and measured performance and satisfaction and the integrity of this implanted system with the in the growing limbs. We did there was also looked at the integrity of the system with growing limbs. I'll show you some data about that, because I have to have at least one legitimate data slide to, you know, talk science.

So, the -- this -- again, this was the system that was implanted in the abdominal area and had the transmitting coil that was taped held with a Tegaderm and onto the over the implant, on the outside. And the person used a different either a walker or crutches to walk. And so, they had bilateral ankle-foot orthoses to protect the limb. And then, they you can see here a thumb switch that the person used to activate a sequence of actions of each leg, movements of each leg. So, they'd hit the switch one way, and it would trigger one leg; or they could trigger a swing-through, walking. They had different sequences that they could program. And I won't go through the details of this, but that's sort of a just a rough drawing of the muscles that were implanted; basically, four on each side. Okay? And so, you cans see this device maybe sort of lost in the midst.

So -- but, look at this and I had forgotten this, and this so, this gave me a good chance to go back and talk to them and review this. The so, the age at the implant some of these kids, 8 years old. And Shrine, of course, as you probably know, can see people up to 21 years old -- and follow kids up to 20 they had permission to follow kids, I think, up to 23 years old -- 2 years, if they were implanted late in their career. But, kids anywhere from 8 up to 20 were receiving these lower extremity implants; again, under a, you know, IRB/IDE-approved study.

And what they found is significant improvement in reduction of time versus this is versus the lower leg brace, whatever that lower leg brace was -- in terms of using the device and doing using it to stand and reach, and doing transfers. Some other activities that were so, it was not intended to be a walking system; it was only intended to be a stand-and-reach system, and that's what it enabled the kids to achieve.

So, in these subject-reported preferences for activities, these were, you know, this was the preferred way to do it, other than a -- you know, a lower leg brace. But, let's say that there's 9 percent that -- you know, that felt -- you know either way.

But, so, of those who made the decision, these neuroprostheses for these standing functions were, you know, pretty important to them. And what the users report is that they could stand up and reach objects, they could do -- you know, work at a sink, they -- eye-to-eye with friends. Writing on a chalkboard is shown here, et cetera. So, pretty important stuff. And I think we already have done that. So, it really becomes an adjunct to the wheelchair.

So, I'm going to talk, in a second, about some of the -- you know, some of the challenges that we faced with that, and because I think that really gets to the heart of it.

I'm just going to do one more thing. This is the Vocare system. And they also did they implanted this Vocare system, which was the Brindley-Finetech system. And what this does is, it stimulates the sacral some of the sacral roots to produce voiding and continence. That's its and that received a an HDE. The Freehand, when it was approved, was before the HDE mechanism, so it had a PMA. And but, this had a and it was not approved for less than, I think, 18 years old. I can't remember exactly. But, this had a has an HDE for kids over 14, I believe. Is that right, Kristen? Okay, thanks. And so, there were two kids, that I was able to identify that were implanted, that were 14 years old. And the performance of this was not significantly different than adults, in terms of the -- you know, the voiding volumes, the amount of residual urine that was left, and, you know, the other measures of satisfaction.

And so, just to give you an idea -- okay? I'll see if I can do this. Right? Okay. So -- but, this is for this is not from a child, this is from adult from an adult. But, you can see here so, this is the bladder, and you can see the urine being expelled through the urethra okay? as a result of that stimulation, and get an idea of how the -- you know, the bladder volume decreases as a result of this. So, this is important stuff. Right? So, a lot of these kids can now be catheter-free.

This is particularly important for women okay? who really do not have a good urinary collection system.

And, let's see, where do I go now? Is this one? Yeah. Okay. So, I did it.

Okay. So, what did we learn? Well, of course, I think as you get the you get the idea for this -- the benefits were exceptional for these adolescents. And I found it to be surprising and I was talking to Dodie but that that lead extension was not a problem. We studied this in animals ahead of time. There's a paper that I have with me. But, leads, properly coiled, would come would extend. And I'll show you that. But, the kids would sort of play around with these devices. Okay? And we had one that was a reoperation with that the child had actually done twiddling and, you know, it kind of "twiddling" right? is the correct term that you use for pacers, right? And, you know, it required us to go back in and -- you know, and untwine the leads and revise, sort of, the adherent technique that we did.

The size and location of the devices some of these are, you know, sort of pretty obvious. The size and weight of the IPG, and the location was necessary. I'll show you where we put these devices. And the size and the weight of the external components was particularly important. Of course, you know, to take things down and decrease them in size is extraordinarily expensive.

And oops okay. So, here are I listed these out before, some of the considerations that we felt were important. And I talked about I just read this slide this morning. So, I've already talked about the size, weight, and positioning of the implantable components. I also found that we've used these encircling nerve electrodes of different types. These we've we have in non-adolescents in adults -- right now; many of them in IDE's approved studies. These were preparing to do but, a lot of these leads that we use are encircling of the nerve. And I've we've all been concerned about what this means, in terms of those electrodes and the formation of connective tissue and, you know, potential compression of the nerve. And I think that we have some special considerations that might be involved in growing children, with these form of technology. So, I think terms of the pediatric applications, we need to examine that more completely.

I'm going to say some things right now about the lead management. And so, here is one of the kids that had the Freehand implant. You can see usually, the Freehand implant would have been placed up in the axillary area, but there wasn't much area there. So, we placed this down in the abdomen. And then we had those long leads. But, we found that these leads, if properly, you know, sort of coiled we did the animal studies on this before doing implants -- but, if properly coiled, they would actually grow out long -- you know, long distances. So, I actually am very, very surprised that these leads will unravel. But, I'm we've never had well, we haven't had much experience that would give us any reason to believe that they you know, that this is a major problem. It might be an issue, but as we get more experience with this. But, in seven growing children with these kind of limb lengths, we could only identify, you know, maybe one electrode that failed, due to nerve growth. And so, that's in addition to the animal studies, which went on before doing those human studies.

The external components have, you know, the environment you we've talked about this a lot. So, minimization -- I think, actually elimination -- of external componentry should be our goal absolute elimination of goal. I don't see any reason why the technology cannot -- you know, cannot accommodate that. And I'll show you an idea that we are working on that we're actually going to be coming to the FDA sometime toward the end of the year about.

But, okay, so then there's, of course, the backward-forward compatibility for replacement. I think this is really a big issue, particularly for the pediatric population, where we're going to be doing these things at 8 years old, let's say, and, you know, maybe at the age of 80 somebody might have some of those components. So, we really have to think very hard about this compatibility of these components and how we deal with these things. I think we can only we cannot, you know, take uncoil cuff electrodes, like these, from around nerves, you know, 50 times. That's for sure. So, the compatibility forward compatibility is going to be important. And we've already talked about some of these issues of imaging, particularly MRI.

So, this is, you know, sort of these were our primary learning experiences. Some of this is on -- you know, on reflection. But, we learn a lot. A lot of our experience now we're very fortunate to have the capability to design and develop these devices in-house that have where our technology can actually be human-grade devices, and take them into the clinic. And so, the feedback of from the clinical experience can drive a lot of our knowledge. It's very, very it's incredibly powerful for us.

So, our the way in which we think about the system -- the future of these designs really has to do with thinking about these distributed systems. And the way that we've approached this, particularly for people with spinal cord injury, is with a network technology and I'm just going to show you a linedrawing of this which is fully implantable and scalable. But, at the with the knowledge that we have now of the communication and powering technologies, I think, for so many of these devices, it's powerful enough to do amazing things. And so, our approach has really been, essentially which we are now in -- you know, beginning to do preclinical testing on -- is to have a central power port with a network cable. So, think of this as your computer. Okay? And this is your CPU. And this has a power source in it. And it's rechargeable. And it can be programmed and communicated to, externally. So, that means bidirectional kind of information flow, the kinds of things that we've talked about today. And onto that network cable, which can be extraordinarily reliable these you know, with new material and techniques I mean, millions and millions of cycles of testing -- onto that cable we can attach different modules that have different capabilities.

And so, in this example I just have to look at it and remind myself this kind of module would be a sensor module. This kind of module, a red module, would be a stimulator module. And there could be multiple leads going from these devices. Now, as it turns out, that through this design of these devices, by putting by -- we because we have short leads, then growing makes less difference to us, because we always put little, you know, loops in things. And with these longer leads, we've actually daisy-chained them together, not exactly the way that's shown here. And so, we can daisy-chain things in a way to -- you know, to accommodate growth, as well.

And so, when we think about these -- you know, this technology, we think that scalable technology could have an amazing impact on the future. So, for people with spinal cord injury, the way we the things that we're trying to do is are to develop systems that can restore the multiple functions that people need. We just received a big a very nice award from NIH to do multi- to test these in multifunctional neuroprostheses -- for hand grasp, for cough, for bladder control, and for postural stability.

So -- you know, so but, I think that this approach could be more globally useful to the kinds of things the broader kinds of things that we've talked about today.

I would say, one of the things just to finish one of the things we haven't talked about are really the challenges of once you have these kind of designs and all of really having -- you know, getting them from, let's say, the -- you know, the -- you know, the initial small-scale implementation into the broader clinical acceptance. And that is no small challenge, particularly for, you know, sort of these Class III devices, and the costs that are part of getting these through clinical trials. But, I think that we have, you know, incredible opportunities to sort of use these advances of technology to address a lot of the issues that we've been talking about today.

So, I'll just finish by saying -- so, I -- you know, I think that these things are probably self-evident from what I've said today. So, thank you all very much.

[Applause.]

DR. PENA: Thank you, Dr. Peckham.

Is there any questions from the panel?

VOICE: Lead the discussion.

DR. PENA: Sure. Just two observations: I think it was keen observation that, you know, the goal should be elimination of at least external technologies for pediatrics. I think that's something that the patients would look very much forward to.

And then, also, you made the observation that there are examples of devices where there's been translation of those parts from the adult to the child, and the safety profile has been protected. There's been no, you know, significant deleterious outcomes. So, I think that's just worth acknowledging, that, you know, you

DR. PECKHAM: That -- yeah, and that's correct, you know. And so, the way I think about this is, think about what we could have done if we had designed those with those needs in mind. Right? Instead of backed into it.

DR. PENA: Dr. Friedman.

DR. FRIEDMAN: Just a quick question. Is the heat generation likely to be an issue when you have multiple -- heat generation from the devices --you know, from the control device?

DR. PECKHAM: Okay. So, it heat the question is about heat generation. And the heat generation, largely, is in recharging. And it's a absolutely critical issue. And it has to be addressed. And so, yes, because we have let's say, with these, we have rechargeable power supplies, rechargeable batteries inside the device, and we have finite amount of time in which we can recharge the batteries. And so, that means we have to we want to drive as much recharging in as short a period as -- of time as possible. But, in doing that, it can generate heat. So, that's one of the important design considerations. There are actually guidelines that exist, in terms of the temperature increases that can be tolerated for these kind of devices. So, yeah, it's one of the important engineering considerations, absolutely.

DR. FRIEDMAN: Those temperature tolerances, is that an age-dependent I mean is it a tissue a surface-area phenomenon, or was it something else?

DR. PECKHAM: It's related to the materials, to the depth of penetration, and the size of the device. Of course, you know, at one end, you want to make the device as small as possible; but, if you do that, you know, you have the opposite end of the -- you know, sort of the you'd like to have a you know, the optimal design would be a larger coil. Okay? So, they -- you know, there's an optimization that's involved in that kind of engineering design.

DR. FRIEDMAN: Just also a followup question. One of the problems that was that has occurred in the past in younger children with devices has been the fracture rate of these devices. And hence, sometimes we purposely implant them in the abdomen to get more coverage, even if there is, potentially, space, you know, higher up. Is that that's obviously -- would be a similar consideration, I would imagine, with the prosthetics that you do.

DR. PECKHAM: So, we'd so, the so, what we you see I showed all spinal injury examples today. And what we wanted to do, and where we started -- you know, it's -- and it's our comfort zone you know, was to work in sensate areas. And that's what drove the implantation up in the axillary area, because the patient was sensate there. So, moving down below has not did not introduce any difficult problems. But, that's why we started up in the axillary area. Because, you know, these are mid-cervical-level injuries. They could feel, basically, down to the chest level.

Yes?

DR. TILTON: Extension of that heating issue: When you have an antenna, basically like that, and you start using imaging, such as MRI, do you find that that could be a bigger issue? We're always taught that the longer, basically, the wire or the antenna, the higher the heat probability in imaging and things. No?

DR. PECKHAM: Yeah. So, I you know, actually, I'm one of those people that has a difficulty in hearing in this room.

DR. TILTON: Oh.

[Laughter.]

DR. PECKHAM: So, if I'm looking at you

DR. TILTON: I thought

DR. PECKHAM: I didn't hear the

DR. TILTON: "bad question."

[Laughter.]

DR. TILTON: No, I'm coming back around to that. Basically, these become antenna, these long wires

DR. PECKHAM: Yes.

DR. TILTON: is my understanding. I'm not an engineer. And one of the places where we face, as a clinician, is when we're trying to image. Let's say you're having a fracture problem, you're having some kind of issue, particularly with MRI, then all of a sudden it would negate body, practically, because of the fact that you could have heating in imaging problems.

DR. PECKHAM: Yes. Yeah. So, we haven't, I think in it would be fair to say, in this neurotechnology field where we have you know, the general approach is to have metal encapsulates for the devices. And that's sort of the standard approach. Then we're -- then we will have that kind of problems with -- you know, with imaging. I think that but, there have been some some advances have been made, in packaging, that give some sort of suggestion that maybe we'll be able to have nonmetallic encapsulation techniques. But, I think it's a long road to go to get those sort of new -- you know, new approaches introduced as sort of the common let's say, a common standard, or even an accepted standard, right? So.

DR. PENA: Thank you again.

[Applause.]

DR. PENA: Okay. So, I think we're going to open up the discussion a little bit to panel.

Dr. Krauthamer, do you want

DR. KRAUTHAMER: I just wanted to segue into the discussion now. It's fitting that Dr. Peckham gave a talk at the end. At the beginning, we heard from our center director, Dr. Shuren, who talked about needs for innovation, especially as related for special needs in pediatric devices.

And through the day we've heard a number of areas in engineering and in the science that could use some innovation. One is device longevity. These devices go in for a very long time. We want to decrease reimplantations. You can't always pull a device out and reimplant it. Backwards compatibility we don't want abandoned devices or devices where the company no longer exists, and there's no way nothing we can do about it, other than putting in a new device. We heard, especially with the shunts, about external monitoring to test for malfunction. That's a very important area that I think is certainly tractable in engineering. Imaging, especially MR compatibility, are is essential. There's almost a 100-percent chance that anyone is going to have an MRI sometime in their lifetime.

We just heard about modular systems, which are good, and -- because on injury, one spinal cord injury, can affect many different body functions, and it makes more sense to have a single modular system that can be used for many functions than to have just a separate implant for each individual function.

We heard about uses for especially with remote patients, with telemedicine. So, devices that are compatible with telemedicine. And also, going along with modular and telemedicine is interoperability between devices and communication systems.

We also heard about size as a major factor in the pediatric system.

So, for a discussion topic, I'd like so, start a discussion of what can be done to encourage innovation in these areas. There is, of course, research. There's training of biomedical engineers and other people who are involved in these devices. Most importantly are market demands. A lot much of what we do is driven by the market. And there's also the issue of what FDA can do, as Dr. Eydelman talked about. We review what we receive from the manufacturers. We can't tell a manufacturer how to innovate a device.

So, those are all questions. I don't know Dr. Peckham has had experience as a medical device innovator and has gone through several cycles. I don't know if you have any thoughts.

DR. PECKHAM: So, yeah, of course I do. I would say that you know, so it's difficult to -- you know, from what I've seen, to stimulate the industry to -- you know, to focus on -- I'm thinking, particularly on the -- you know, sort of the pediatric population, because, by and large, you know, so much of it becomes orphaned right? I think, you know. And so, it seems to me as though one of the things that we have to do is think about those ways in which we can enable a larger demand to create an opportunity for the -- you know, for the -- you know, for the smaller populations. And I would say that's sort of our thinking, in terms of actually, in terms of all spinal injury. Okay? For example, something that's near and dear to what I'm -- you know, want to be sure is available to people.

So, that actually, you know, was some of what was, you know, involved in the -- you know, sort of the thinking of the -- of these modular techniques not only how can you meet the -- you know, a small demand, but where might there be other indications that it -- you know, that it might be -- you know, that it could be viable and -- you know, and drivable?

And, you know, so, you know, for example, one of the things that people have -- are working in the DBS community have said is, "We need to have the capability of sensing and stimulation, sensing in multiple -- you know, multiple functions and, you know, in a -- sort of a distributed way." that's not exactly the words that you'd hear but, "in a distributed way, and having more flexibility in multiple sites in which we act you know, in which we can, you know, activate, and maybe even that we can not only deliver, you know, electrical current, but also, you know, some sort of pharmacological agent."

So, you know, that's sort of in the you know, in the back of our thinking is that or, maybe at the base of our thinking, you know, is being creative in the design that enables multiple things to happen so that the technology for the smaller indications can be more easily driven. And because, otherwise, I think it's a -- you know, it's such a hard road anyway.

But and, you know, if so, could I just sort of say another thing? I think what you do with the orphan products, you know, opportunity that you create is incredibly important in this -- you know, in this area. And I don't know the level at which people respond to the -- you know, to that opportunity. You know, so maybe one of the things that -- you know, that could be -- you know, could be enhanced is -- you know, in the context of what FDA can do is -- you know, is, if these pediatric applications are -- you know, are going to be really important to us, which I hope they will be, you know, then -- you know, then maybe create some -- you know, some more knowledged opportunities for -- you know, for them that you know, special kind of programs that you might do to encourage that kind of work.

DR. EYDELMAN: If I can just add. And that's exactly one of the reasons I wanted to highlight the HDE process. And even though it's been around for a long time, all together there have only been 55 HDE approvals to date. So, it is not the pathway that is really, I feel, fully explored. And a lot of the patient populations that we were discussing today would qualify under HUD designation.

So, for those of you with ties to the appropriate community, do you -- do think of it as a potential for going forward.

DR. MARKS: You know, in working with these devices as a clinician over the years, it intrigues me that there is virtually no compatibility from generation to generation from the same company, and never mind between companies. I mean, it's as bad as cell phones. Every cell phone manufacturer has a different connector to their cell phone. And I don't really understand why there can't be some standardization so that -- you know, even with the currently approved device on the market, as they went from generation one to generation two of the generators, the connectors changed and the lead extensions changed. So, now if you want to change, you've got to do a more extensive surgery, or you've got to put in an adapter which is as bulky as the device itself, making it a not very tenable process to change out something to a longer-lasting device. But, it seems to me and I understand the companies need some time to develop their product; they've invested a lot of money in these things but, you know, if you had a universal adapter -- if somebody came out with a better, more creative lead system, for example, that you could attach to an existing generator, then I think that type of competition would actually be very helpful. And you wouldn't be tied into, you know, the one company all the time if something better came along. And you'd get people who could develop pieces of it that might fit together better to meet the patient's needs.

DR. EYDELMAN: If I can just add this is something that I kept thinking throughout the day also. This area of device development is essentially not represented in the ANSI, which is American National Standards Institute. And under that body of organization, we actually have gone very far in developing national standards for particular type of devices. And then, the American body usually takes it to the ISO, the International Standards Organization.

So, I would urge, for those of you who feel the same way, to perhaps make a petition to ANSI. There's a formal process, where you can ask to open a new workgroup for a particular item. And it's a very straightforward process. And we have done great, great we have made great strides utilizing ANSI process in other arenas.

DR. PENA: Dr. Friedman?

DR. FRIEDMAN: Yeah, I just wanted to add on a little bit to what Hunter said about I think that looking at extending applications for these devices is absolutely crucial. And that really gets back to the clinician side of it, rather than, necessarily, device manufacturer side. Looking at novel ways, for example, to use if you use, for example, deep brain stimulation, not just within dystonia but within spasticity, looking at different areas of the brain, for example, to stimulate, which can reduce spasticity. Because once you start adding in spasticity to things like dystonia, your population is actually really very, very large within the pediatric world.

The other is always gets back to risk. And, you know, one of the reasons that immunization became so successful was that there was the indemnity fund essentially set up for immunization. And you wonder, with some of these orphan devices and orphan development, whether there shouldn't be some kind of similar I think one of the things that manufacturers are always very reluctant to is the risk factor, because it carries with it it's not just a year or two, but it's a lifetime, especially in a developing child, that they don't want to be exposed to. And you sort of wonder what is available out there.

I think the last thing that I'll say is that I think we also really have to try and understand the disease processes a little better, because, at the moment, it's still a very crude shotgun approach to most of what we do. And I think what we're seeing, for example, if you look at the hydrocephalus world and again, I know this is perhaps a slightly different discussion, except it still comes into this age range is -- fetal intervention, these days, with devices, is becoming a really big market. And it's becoming targeted not just for pediatric cardiologists, but also there's a -- extensive literature, in the past, on shunting in utero, where you can actually impact brain development and really do something about outcome, again. And the technology's just not there. And so, the studies, to date, that have been there for fetal intervention has just not worked. But, I think, again, the problem is not that motivation for that development to take place, and understanding, both from a device side, why it doesn't work in utero when it works outside. So.

DR. PENA: Other comments?

DR. PECKHAM: Could I just make a kind of -- I think that one of things that we've found, in talking to our clinical colleagues in a number of fields -- in urology, in neurosurgery, in, you know, orthopedics, in -- you know, in particular -- is that particular is that many times the technology, you know, that exists -- you know, as it exists from the commercial manufacturer, is really not up to the job. And I don't mean that it's -- you know, that it's bad technology. I don't in any way mean to, you know, suggest or infer that. It's incredible technology. But, it -- you know, but there's not a high level of flexibility that it has. And so, that level of flexibility that's inherent in it, because it's -- you know, sort of has single-purpose, you know, intention, largely -- you know, is what I think is one of the factors that's limiting sort of driving the field, including maybe doing the -- you know, sort of the pediatric area. And, you know, so I think that we have to, you know, sort of enable the clinical community to have -- you know, to have resources; you know, one of them being technology that enables the sort of, the innovativeness of the clinical community to test new -- you know, new things that you want to do -- right? new you know, new -- you know, to address new clinical problems, or different or the same clinical problems, better, you know. And I think that right now we're sort of up against the wall with the -- you know, without having those enough of the tools that we -- you know, that we need.

DR. PENA: Dr. Pearl?

DR. PEARL: I just wanted to mention that it seems we're on the thrust of explosion in neurotechnology. I mean, the engineering type of prostheses that you're describing, that I've seen at meetings, in terms of robotics, the what we expect to see in deep-brain stimulation for other indications, such as epilepsy or psychiatric indications. And then, if you think about with in the military, the needs of the veterans, you know, coming over the active military are so enormous. And then, the funding in defense is high for this kind of work. So, it's an opportunity. But, I mean, this field is just going to is on the cusp of an explosion.

And one thing that might be helpful -- and you've probably looked into it -- is whether the FDA could direct or ally or partner with defense, in terms of the kind of investments they make in this sort of technology, looking at it in populations that simulate our pediatric population or our vulnerable populations handicapped, those with cognitive impairment, those with a combination of physical and neurological morbidities -- because these guys coming over injured obviously have combinations of morbidities. But, this little meeting here is just the tip of the iceberg, in terms of what's coming down.

DR. KRAUTHAMER: Just to answer your question, we are partnering with the Defense Department in several ways. There's this DARPA Revolutionizing Prosthetics Program, and we're involved in that. And that's the modular limb, and neural control of that limb.

And we also have some of the same goals. They're concerned about neuroelectrical interfaces and why they fail. So are we. I mean, we want safe, long-term use for it.

We also have some laboratory operations that will help with some of the confirming some of the DARPA results and coming up with test methods that will be useful to them. So, we've reached out to them, and they're happy to have us participate.

DR. WALTZMAN: Is there a way to kind of have a two-tiered system of review and of approval, in terms of certain devices? For instance, cochlear implants very often their modifications or enhancements to their devices are software-based, not hardware-based, having nothing to do with the electricity being delivered, nothing to do with the electrode array. And most often, it's external processing strategies.

In the U.S., we seem to be sometimes getting those upgrades, so to speak patient upgrades a year or two after they are essentially brought out. And obviously I don't -- there are some that should be studied in depth. But, there are others that are simpler in nature.

Is there some way, perhaps, to consider getting to the market these upgrades for the children and the adults, as well, and differentiating between a serious upgrade and a not-so-serious upgrade?

DR. EYDELMAN: Okay. From the nod, I'm getting this one.

So, the regs and the laws dictate how the devices are regulated, as far as classifications and as far as the timeframes for review of each kind of a supplement.

Having said that, we always are learning. We're always learning and we're always fine-tuning what requires what kind of a dataset. And we definitely have tiers of, let's say, this kind of a submission always needs a clinical; this kind doesn't always need a clinical, it needs this kind of a and again, we actually delineate that in some of the standards for other device areas, just to come back to the ANSI my earlier ANSI comment.

Having said all that, I want to point out, on the flip side, I'm proud to say that after being a U.S. delegate on ISO for many, many years, I can attest to the fact that FDA's system does indeed protect the public to a much greater safety level than in any other country, and that very often, yes, they got to the market faster, but they were also removed from the market very fast, because nobody bothered to look.

So, I'll end there.

DR. PENA. So, I think, why don't we try to bring this all together. I know there's been a lot of different discussions, and I think we're at a point where we can make, maybe, some generalizations on some of the data that we've shared and some of the perspectives that have been shared.

Basically, at the beginning of the workshop, we gave the purpose, and it was to solicit information directly from academics, clinicians, public health advocates, pediatric users of these devices, and their representatives, and Federal Government representatives associated with use, research, and development of pediatric neuroprostheses. This is unfortunately, that's not the that's the other slide presentation. But, some of the workshop themes that I think we've heard, and that go to the first question that Kristen presented, which was, What are the best approaches for enhancing the protection and promotion of public health in children and adolescents with neuroprostheses? -- I think there are places and times to have very detailed discussions on specific device specific medical devices. But, I think it also is helpful to have, at these type of workshops, where there is a look across the device area to see where there are these considerations that may be applicable.

So, we've heard about, for general considerations, pediatric subpopulations are important. There was some discussion about age classifications and whether, you know, there's a disability, if it's a static or if it's a fluid condition, that there should be considerations for those changes that will be needed.

There are lifelong challenges and considerations that may need to evolve for the children and adolescents over time, and that "efficacy" and "effectiveness" may have different meanings.

There also was the comment about -- different regulatory needs may exist for different device types. And I think that's certainly true with some of the devices that we've talked about today.

For specific device considerations, I think some of the themes have been: longevity, making smarter devices, adaptability of a device to the child, and looking at malfunction, unanticipated adverse events, and impact upon the pediatric quality of life.

If we look at the look at to the output, I think, while we have a meeting transcript that will become available there will be a meeting summary and, of course, we'll have the public docket open for comment, so that folks can submit comments following the meeting, you know, as ideas come to mind -- I think there's been a good deal of discussion here today that has helped the agency hear about all the different perspectives. That was the goal of today's workshop.

So, the future goals are to continue to develop pediatric guidance. I think we had a nice start to that. And I think, as these device areas continue to grow, and especially in the neuro area, the emerging science, I think there will be future opportunities to have further discussion about more specific pediatric guidance; to continue evidence-based assessments to address unmet needs for the pediatric population; and also to develop pediatric registries that was also mentioned as a way to collect information for these different conditions and disorders; to collect data on device use in children.

Before we close, I would just like to mention -- give some thanks to the people that were helping in putting this workshop together. Courtney Treece, back -- has has been very helpful in getting this workshop sort of tied up. And a lot of the staff here, the FDA staff Drs. Krauthamer, Joy Samuels-Reid, John Chelonis, Neil Friedman -- who are on this Pediatric Action Committee and who meets once a week to talk about the steady progress -- I think these meetings don't happen without their ownership and responsibility. And so, for that, I'm very grateful.

And I think that's it. I'd like to close the workshop and thank everybody.

[Applause.]

[Whereupon, at 4:35 p.m., the meeting was adjourned.]