FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

PEDIATRIC SUBCOMMITTEE

OF THE

ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

8:05 a.m.

Tuesday, April 24, 2001

 

 

 

 

 

 

 

 

Food and Drug Administration

ACS Conference Room, Room 1066

5630 Fishers Lane

Rockville, Maryland 20857

ATTENDEES

SUBCOMMITTEE MEMBERS:

P. JOAN CHESNEY, M.D., Chair

Professor of Pediatrics

Department of Pediatrics

University of Tennessee College of Medicine

50 North Dunlap

Memphis, Tennessee 38103

JAYNE E. PETERSON, R.PH., J.D., Executive Secretary

Advisors and Consultants Staff (HFD-21)

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, Maryland 20857

JUDITH O'FALLON, PH.D.

Director, Cancer Center Statistics Unit

Plummer #4

Mayo Clinic

200 First Street, S.W.

Rochester, Minnesota 55905

 

SGE CONSULTANTS:

DAVID DANFORD, M.D.

Associate Professor of Pediatrics

University of Nebraska Medical Center

Pediatric Cardiology

600 South 42nd Street

Omaha, Nebraska 68198-216

KATHRYN EDWARDS, M.D.

Professor of Pediatrics

Vanderbilt University

1161 21st Avenue South

7th Medical Center North

Nashville, Tennessee 37232

ROBERT FINK, M.D.

Pulmonary Medicine

Children's National Medical Center

111 Michigan Avenue, N.W.

Washington, D.C. 20010

ATTENDEES (Continued)

SGE CONSULTANTS: (Continued)

SUSAN FUCHS, M.D.

Children's Memorial Medical Center

Division of Pediatric Emergency Medicine

2300 Children's Plaza, No. 62

Chicago, Illinois 60614

RICHARD GORMAN, M.D., FAAP

Pediatric Partners

9051 Baltimore National Pike

Ellicott City, Maryland 21042-3927

MARK HUDAK, M.D.

Professor and Chief

Division of Neonatology

Department of Pediatrics

University of Florida at Jacksonville

Health Sciences Center

653-1 West 8th Street

Jacksonville, Florida 32209

ROBERT NELSON, M.D., PH.D.

Department of Anesthesia and Critical Care Medicine

The Children's Hospital of Philadelphia

34th Street and Civic Center Boulevard

Philadelphia, Pennsylvania 19104-4399

KEITH RODVOLD, PHARM.D., Consumer Representative

Professor, Department of Pharmacy Practice

University of Illinois at Chicago

College of Pharmacy M/C 886

833 South Wood Street, Room 164

Chicago, Illinois 60612-7230

STANLEY SZEFLER, M.D.

National Jewish Center

Division of Clinical Pharmacology

1400 Jackson Street

Goodman Building, Room 926

Denver, Colorado 80206

ATTENDEES (Continued)

SGE CONSULTANTS: (Continued)

LEROY WALTERS, PH.D.

Georgetown University

Kennedy Institute of Ethics

Philosophy Department

37th and O Streets, N.W.

4th Floor, Healy Hall

Washington, D.C. 20057-1212

 

GUESTS AND GUEST SPEAKERS:

MURRAY GOLDSTEIN, D.O.

Medical Director

United Cerebral Palsy Research and

Educational Foundation

1660 L Street, N.W., Suite 700

Washington, D.C. 20036

ROSS HAYS, M.D.

Children's Hospital (CH-71)

4800 Sand Point Way, N.W.

Seattle, Washington 98105

BELINDA HURLBURT

29 Arthur's Lane

Stafford, Virginia 22554

RALPH KAUFFMAN, M.D.

Representing American Academy of Pediatrics

Director, Medical Research

Professor of Pediatrics and Pharmacology

The Children's Mercy Hospital

University of Missouri at Kansas City

2401 Gillham Road

Kansas City, Missouri 64108

ERIC KODISH, M.D.

Director, Rainbow Center Pediatric Ethics

Associate Professor

Pediatrics, Oncology and Biomedical Ethics

Rainbow Babies and Children's Hospital

11100 Euclid Avenue, Room 340

Cleveland, Ohio 44106-6054

ATTENDEES (Continued)

GUESTS AND GUEST SPEAKERS: (Continued)

MARIA PENA, M.D.

Department of Otolaryngology

Children's National Medical Center

111 Michigan Avenue, N.W.

Washington, D.C. 20010-2470

STEVEN SPIELBERG, M.D., PH.D.

Representing Pharmaceutical Research and

Manufacturers Association

Janssen Research Foundation

1125 Trenton-Harbourton Road

Titusville, New Jersey 08560-0200

SCOTT STIEFEL, M.D.

Assistant Professor

University of Utah

Departments of Pediatrics and Psychiatry

Neuropsychiatric Clinic for People with

Development Disabilities &

The Neurobehavior Clinical Research Program

546 Chipeta Way, Suite 459

Salt Lake City, Utah 84108-0887

BENJAMIN WILFOND, M.D.

Office of Bioethics and Special Populations Research

Department of Clinical Bioethics

National Institutes of Health

Building 10, Room 1C118

9000 Rockville Pike

Bethesda, Maryland 20892-1156

JONI WOERLY, R.N.

State of Florida Department of Health

Children's Medical Services

910 North Jefferson Street

Jacksonville, Florida 32209

ATTENDEES (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

LISA MATHIS, M.D.

Medical Officer

Division of Dermatologic and Dental Drug Products

DIANNE MURPHY, M.D.

Associate Director of Pediatrics

Center for Drug Evaluation and Research

JOHN V. KELSEY, D.D.S.

Clinical Team Leader

Division of Dermatologic and Dental Drug Products

C O N T E N T S

ISSUE: CLINICAL DEVELOPMENT OF PRODUCTS

FOR DROOLING IN NEUROLOGICALLY IMPAIRED CHILDREN

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

by Ms. Jayne Peterson 11

BACKGROUND INFORMATION AND OVERVIEW

by Dr. Dianne Murphy 13

REVIEW OF MEETING AGENDA/INTRODUCTION TO THE ISSUES

by Dr. John Kelsey 15

PHARMACOLOGIC CONTROL OF DROOLING

by Dr. Lisa Mathis 22

QUESTIONS FROM THE SUBCOMMITTEE 31

ETHICAL ISSUES IN PEDIATRIC RESEARCH:

ANTIMUSCARINICS TO CONTROL THE MEDICAL

AND PSYCHOSOCIAL COMPLICATIONS OF DROOLING

by Dr. Benjamin Wilfond 41

MEDICAL/SURGICAL MANAGEMENT OF DROOLING

by Dr. Maria Pena 49

ASSESSMENT/METHODS FOR CAPTURING INFORMATION

FROM THE PATIENT

by Dr. Ross Hays 58

QUESTIONS FROM THE SUBCOMMITTEE 67

AMERICAN ACADEMY OF PEDIATRICS PERSPECTIVE

by Dr. Scott Stiefel 80

SCOPE OF THE PROBLEM

by Dr. Murray Goldstein 95

PARENT/CAREGIVER PERSPECTIVE

by Ms. Belinda Hurlburt 101

OPEN PUBLIC HEARING 115

QUESTIONS FROM THE SUBCOMMITTEE 116

C O N T E N T S (Continued)

AGENDA ITEM PAGE

PRESENTATION OF ISSUES

by Dr. John Kelsey 139

SUBCOMMITTEE DISCUSSION OF ISSUES/QUESTIONS 142

CLOSING REMARKS

by Dr. Dianne Murphy 184

P R O C E E D I N G S

(8:05 a.m.)

DR. CHESNEY: I'd like to welcome everybody this morning to this session on clinical development of products for drooling in neurologically impaired children.

I think we'd like to start with the introductions, and why don't we start right here with Dr. Kelsey.

DR. KELSEY: My name is Jake Kelsey. I'm the dental team leader in the Division of Dermatologic and Dental Drug Products in the Center for Drugs at FDA.

DR. MATHIS: I'm Lisa Mathis. I'm a general pediatrician in the Division of Dermatologic and Dental Drug Products at CDER, FDA.

DR. RODVOLD: Keith Rodvold, Colleges of Pharmacy and Medicine, University of Illinois at Chicago.

DR. FUCHS: Susan Fuchs, pediatric emergency medicine, Children's Memorial Hospital, Chicago.

DR. DANFORD: Dave Danford, pediatric cardiology, University of Nebraska Medical Center and Creighton University Joint Division.

DR. EDWARDS: Kathy Edwards. I'm from the Department of Pediatrics, Division of Infectious Disease at Vanderbilt University in Nashville.

DR. GORMAN: Rich Gorman, general pediatrics, Ellicott City, Maryland.

DR. SZEFLER: Stan Szefler, Department of Pediatrics, University of Colorado in Denver.

DR. NELSON: Robert Nelson, critical care medicine at the Children's Hospital, Philadelphia.

DR. O'FALLON: Judith O'Fallon, statistician at the Cancer Center Statistics Unit, Mayo Clinic, Rochester, Minnesota.

DR. FINK: Bob Fink, pediatric pulmonologist at Children's National Medical Center here in Washington, D.C.

MS. PETERSON: I'm Jayne Peterson with the FDA. I'm the Executive Secretary of the subcommittee.

DR. CHESNEY: Joan Chesney, the Infectious Disease Division at the University of Tennessee in Memphis and St. Jude's Children's Research Hospital.

DR. HUDAK: Mark Hudak, neonatology, University of Florida, Jacksonville.

DR. KAUFFMAN: Ralph Kauffman, Children's Mercy Hospital, Kansas City, Missouri, University of Missouri.

DR. SPIELBERG: Steven Spielberg, pediatric drug development, Janssen Research Foundation, representing PhRMA.

DR. WILFOND: Ben Wilfond, pediatric pulmonologist at the Department of Clinical Bioethics at the NIH.

DR. KODISH: Rick Kodish, Rainbow Center for Pediatric Ethics, Rainbow Babies and Children's, Cleveland, Ohio.

MS. WOERLY: Joni Woerly, State of Florida Children's Medical Services, Jacksonville, Florida.

DR. GOLDSTEIN: Murray Goldstein, neurologist, Medical Director, United Cerebral Palsy Research Foundation.

DR. HAYS: I'm Ross Hays from the Departments of Rehabilitation Medicine and Pediatrics at the University of Washington and Children's Hospital in Seattle.

DR. PENA: I am Maria Pena from Children's National Medical Center. I'm one of the pediatric ENTs there.

DR. STIEFEL: Scott Stiefel. I'm a pediatrician, adult and child psychiatrist at the University of Utah, Department of Pediatrics and Child Psychiatry, representing the American Academy of Pediatrics, Committee on Children with Disabilities.

DR. CHESNEY: Thank you all very much.

Now Jayne Peterson is going to read the conflict of interest statement.

MS. PETERSON: The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.

Since the issues to be discussed by the subcommittee at this meeting will not have a unique impact on any particular firm or product, but rather may have widespread implications with respect to an entire class of products, in accordance with 18 U.S.C., section 208(b), waivers have been granted to all members and consultants who have reported interests in any pharmaceutical and biologic companies.

A copy of these waiver statements may be obtained by submitting a written request to the FDA's Freedom of Information Office, room 12A-30 of the Parklawn Building.

With respect to FDA's invited guests, there are reported affiliations which we believe should be made public to allow the participants to objectively evaluate their comments.

Dr. Ralph Kauffman would like to disclose that he has contracts and/or grants from Bristol Myers Squibb and he is a researcher for Bristol Myers Squibb, Janssen, and Merck. In addition, he has received consulting fees from Johnson & Johnson, McNeil Consumer Products, and Purdue Pharma, and he is a scientific advisor to McNeil Consumer Products and Purdue Pharma.

Dr. Steven Spielberg would like to disclose that he is a full-time employee of Janssen Research Foundation.

In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record.

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

Thank you.

DR. CHESNEY: Thank you, Jayne.

For all the speakers, if you have a question, please be sure to push the button down and turn the mike on so the red ring is visible, and that allows your excellent questions to be recorded for posterity.

Our issue this morning has to do with agents that will reduce salivation and drooling, and the questions specifically for the committee have to do with safety, dose titration, and ethical issues. Dr. Dianne Murphy is going to start our program with some introductory comments.

DR. MURPHY: I wanted to, once again, thank the committee for their excellent discussion and questions yesterday. You dealt with a chronic disease. I think the word "insidious" was used. It develops over time and is asymptomatic. It has an evolving epidemiology, has therapies that had known toxicities, certainly had ethical considerations in the questions that we asked you yesterday.

Today we have some similarities and some dissimilarities. It is a chronic problem. The efficacy is not the question in this situation. We have a therapy that we know is efficacious that we know is being used. It's the dose. It's the ethics of how do we conduct a trial in a population so we can determine the correct dose because what is happening at the present at least -- you'll hear more about this. What we are understanding the concern is that the dose is being titrated individually for every child in a population that may or may not be able to communicate the discomfort and adverse effects of that titration, dose-finding activity. Or a dose is given and it's not effective, and then the child ends up on other therapies or, as you will hear, other interventions that may or may not have been the best if it turned out the child was really being underdosed.

So, we have an issue that you will hear discussed that we wish to contribute to the knowledge of how to find an appropriate dose, but we think that there are clearly ethical issues in how one would construct the set of trials, and we seek your advice on whether we should move forward in this arena, and if so, how.

Thank you very much.

DR. CHESNEY: Thank you for clarifying that, Dianne. So, we're being particularly asked to address the issue of how to construct trials for this population to determine the correct dose.

Our first speaker will be Dr. Jake Kelsey who is going to review the agenda and introduce us to the issues.

DR. KELSEY: Thank you, Dr. Chesney.

On behalf of Dr. Jonathan Wilkin, who is the Division Director for Derm and Dental, I'd like to thank the subcommittee members, the presenters, and guests for coming here today to help us address some of the issues that impact on the development of drugs in this very vulnerable patient population.

Drooling can be a problem in children with cerebral palsy, as well as other neurodevelopmental defects. There are currently no approved pharmacologic therapies for drooling, though we are well aware that a number of antimuscarinic drugs are used off label for this purpose. As is often the case with off-label use, there are limited studies in this particular indication. Safety and dosing issues remain and formulations haven't been developed for use in this population.

As we know from history, making new formulations for children without well-controlled studies can be dangerous. FDA would like to promote such studies, hence this meeting in which we want to address special considerations in studying drugs in this patient population.

FDA would like the Pediatric Subcommittee to address a number of issues. Assessment of adverse events in this population is first. The appropriate formulations for this use. How to develop useful dosing information for this indication, and also unique ethical and legal considerations that apply to studying this population. And there are more detailed questions included in your meeting package.

A number of people have inquired about why the Division of Dermatologic and Dental Drug Products is the group within the Center for Drugs at FDA that's charged with looking at this issue. So, let me address that.

The dental team within Derm and Dental is responsible for regulating products to treat xerostomia, or dry mouth. The marketed products currently for xerostomia are pilocarpine and cevimeline, and these are approved for use in patients with Sjogren's syndrome and with hyposalivation from radiation to the head and neck.

Because we're familiar with the physiology of the salivary glands and the pharmacology of the muscarinic agonists, it seemed reasonable for us to take a look at the muscarinic antagonists as well. In addition, we're fortunate in our division to have a pediatrician who has treated patients with cerebral palsy and has used glycopyrrolate, which is apparently the most frequently used of these antimuscarinics. You'll hear from Dr. Lisa Mathis in just a minute.

The agenda for the day is included in your handout material. I'll begin by giving a brief review of the neurophysiology of the autonomic nervous system and the muscarinic receptors in particular. Dr. Mathis will then discuss drooling in cerebral palsy patients, addressing the extent of the problem, current treatment issues impacting on conducting clinical trials. Her presentation will be followed by an opportunity for questions and answers to the two of us.

This will be followed by a presentation on ethical issues in pediatric research by Dr. Benjamin Wilfond from the NIH. He is a bioethicist and pulmonologist.

He'll be followed by Dr. Maria Pena, an ENT physician from Children's National Medical Center here in Washington. She'll talk, from the clinical perspective, about the medical and surgical control of excessive drooling.

Next will be Dr. Ross Hays from the University of Washington who is boarded in both pediatrics and physical medicine and rehabilitation, as well as having done a pain fellowship. He'll talk about methods for assessing adverse events in patients who have difficulty communicating.

Following this group of speakers, there will be another opportunity for questions and answers.

Finally, we'll hear from several advocates for patients with cerebral palsy. Dr. Scott Stiefel from the University of Utah is here representing the American Academy of Pediatrics' Committee on Children with Disabilities. He'll be followed by Dr. Murray Goldstein who is the Medical Director of the Cerebral Palsy Research and Education Foundation. The final speaker will be Ms. Belinda Hurlburt. She's the mother of a child, Ronny-Kay, who suffers from cerebral palsy. Both of them are here with us. Ms. Hurlburt will give her insight as someone who every day is involved in the issues that we're going to talk about. Again, there will be another opportunity for questions and answers.

After a break, there will be an open public hearing period and again questions from the subcommittee.

I would also like to acknowledge one person who won't be speaking today, Ms. Joni Woerly, who is from the Florida State Department of Children's Medical Services. As I say, she's not going to be speaking, but she's come here today to offer her experience in treating patients with cerebral palsy.

There are also a number of ethicists here today who are included in your handout. I'd like to thank them also for coming to help us with this issue.

As I said, our goal is to have pharmacologic agents that can control drooling appropriately studied so that they can be safely used in this patient population. While we can't rule out the development of products with novel mechanisms of action, those that are currently used off label target the muscarinic receptors of the autonomic nervous system that innervate the salivary glands.

The autonomic, or involuntary, nervous system innervates the heart, blood vessels, visceral organs, smooth muscles, and of interest today, the secretory glands. The autonomic nervous system is divided into the sympathetic and parasympathetic systems. Most target organs are innervated by both sympathetic and parasympathetic, and these two work in opposite ways to create a balanced response, though in the case of salivary glands, both the sympathetic and parasympathetic systems stimulate secretion of saliva, though the sympathetic stimulation is stronger.

In general, the neurotransmitter for parasympathetic fibers is acetylcholine, and for sympathetic fibers, norepinephrine. However, in the case of the salivary glands, both sympathetic and parasympathetic fibers employ acetylcholine as the neurotransmitter. So, it's clear that any pharmacologic mediation of drooling will have to target acetylcholine receptors.

These are, in turn, divided into muscarinic and nicotinic subtypes. The receptors in the salivary glands are the muscarinic type. To refine things a bit more, the muscarinic receptors in the salivary glands are the M3 subtype.

So, the salivary glands are stimulated by both sympathetic and parasympathetic fibers with acetylcholine as the neurotransmitter in both. The receptors are of the muscarinic M3 type. To reduce salivation, we can employ an antimuscarinic drug, and there are a number of antimuscarinics already on the market for other indications.

These drugs are effective in reducing saliva secretion, and hence will be effective in decreasing drooling. As will be discussed at some length, drooling can be a significant problem in patients with cerebral palsy and other neurodevelopmental defects causing aspiration, maceration of the skin and the associated pain that predispose to secondary infection, and can be a barrier to educational opportunities and placement in these patients.

However, many bodily functions other than the salivary glands are mediated by cholinergic receptors. Unfortunately, we can't be selective in blocking these cholinergic effects. Blocking the cholinergic receptors results in, among other things, dilatation of the pupils of the eye causing blurred vision, increased heart rate resulting in palpitations, decreased gut motility, constipation, urinary retention which, of course, could be painful and cause urinary tract infections. In addition, the patients often experience reduced sweating and loss of temperature control. These effects can be very unpleasant for the patients, as well as, in some cases, dangerous.

Because the response to these agents varies among patients and is dose-dependent, it's important to have formulations that permit easy dose titration, and clinical trials to support marketing of these products should involve careful dose titration.

Also, because muscarinics are not selective and because many patients with cerebral palsy and similar diseases cannot effectively express their discomfort, it's important that clinical studies involving these patients maximize the possibility of identifying such responses for safety reasons.

In summary then, the pharmacologic target for controlling drooling is the muscarinic receptors, and we're well aware that a number of antimuscarinic drugs are used off label for this indication. However, because antimuscarinics are not selective and extrasalivary antimuscarinic effects can be dangerous and unpleasant for the patient, we need studies to safely and properly dose these products. And that brings us to the issue also of the fact that dose ranging and assessment of adverse events is problematic in this particular patient group. So, these are the issues that we would like you to help us with today.

Dr. Mathis will now go into more detail about the problem of drooling in cerebral palsy patients, the treatments, the need for marketed drugs, and the challenges in studying drugs in this patient population.

Thank you.

DR. MATHIS: Hi. I'm Lisa Mathis, a general pediatrician with the Division of Dermatologic and Dental Drug Products.

Today we have several issues for the Pediatric Subcommittee to consider.

The first is that drooling is a problem in children with neurologic impairments, and I'll be discussing drooling and the need to control drooling in this patient population.

Also, I'll be discussing the need for studies of medications and development of medications to control drooling. As you know, currently there are no approved pharmacologic therapies for this indication.

Then finally, we'll be discussing the challenges of conducting these studies and the special considerations that need to be given for studying drugs in this patient population.

Drooling is a significant problem in children with cerebral palsy and other neurologic impairments. Although it's frequently referred to as sialorrhea in the literature, it is not the result of hypersalivation. Rather, it's impaired motor function that results in difficulty swallowing.

The prevalence of cerebral palsy is 1.5 to 2.5 per 1,000 live births, and there are approximately 400,000 to 800,000 children and 400,000 adults in the United States with cerebral palsy.

Of these patients, 25 to 35 percent have some degree of drooling, and approximately 10 percent require intervention. There are also several other conditions associated with drooling in children, to include Down's syndrome, cerebral vascular accidents, hemiparesis, and degenerative diseases such as Rett's syndrome.

The reason drooling requires intervention is that it may lead to aspiration. This can be life-threatening. It can lead to secondary pneumonias and is also associated with chronic pulmonary inflation. It can also lead to maceration of the skin. The large surface area that's involved in this breakdown can be very painful, similar to a burn. It also predisposes to secondary fungal and bacterial infections.

Drooling may also compromise education, and it can do this by affecting attendance. It can affect the patient's ability to use electronic communication devices, and it can also actually take up all of the speech therapist's time. If a therapist is busy trying to work with a child to control drooling, they really don't have time to address other issues. It can also affect placement into special day-cares or special education programs, and this can have a profound effect not only on the child, but the child's family.

There are several methods that are used to control drooling. The first is behavioral. And this is quite effective actually, but some patients have such severe involvement that the behavioral modifications just don't work. There's also pharmacologic, which we'll be discussing in great detail today. And there's surgical, and I'm sure Dr. Pena will be addressing this in a few moments. The surgery involves translocation and transection of the salivary ducts or neurectomies. It's irreversible. Everybody knows that there are a lot of risks associated with surgery, to include anesthesia, intubation, and in these patients who may have many surgeries over their lifetime, there's an increased risk for latex allergy.

As mentioned by Dr. Kelsey, antimuscarinics are commonly used to inhibit salivation in these patients. The most commonly used medications include benztropine, glycopyrrolate, scopolamine, trihexyphenidyl, and several others.

While there's a large body of experience in the pediatric practice using these medications for this indication, antimuscarinics are not approved for chronic use in children. They are approved for acute use in pre-anesthesia in children.

Also, there are no commercially available pediatric formulations, and what this means is every time a parent goes to fill the prescription, individual pharmacists, using the IV solution or crushed tablets, mix these with other ingredients to make a pediatric solution. This can cause problems with dosing. It can cause problems with stability and absorption.

Also, there's limited efficacy, safety, and dosing information from clinical studies.

The reason why dosing is so important in these medications is because of the known adverse event profile. Antimuscarinic effects on the neurologic system include headache, irritability, nervousness, confusion, disorientation, and depression. Special senses can be involved with blurred vision and loss of taste.

The gastrointestinal system can be involved with nausea, vomiting, paralytic ileus, and constipation, and we can see tachycardia and palpitations in the cardiovascular system.

Antimuscarinic effects on the urogenital system include urinary retention and dysuria, and there are several others, to include hyperthermia, due to inability to sweat, and xerostomia. It should be noted that xerostomia is actually the effect that we're looking for here, but not absolute xerostomia. Dry mouth is not only very uncomfortable, but it can lead to oral abrasions and an increase in dental caries.

Clinical trials are necessary to evaluate new formulations. Commercially available formulations would increase safety and consistency in administration, and developing appropriate concentrations would allow caregivers to titrate the dose in small increments.

Clinical studies are also necessary to determine pediatric dosing. We know, in indications other than in drooling, the optimal dose must be individualized. The response is variable from patient to patient. In the studies that we do have on children with drooling, we know that the degree of drooling at baseline is a poor predictor of response to these medications. Small dose adjustments must be made until the benefit is achieved or side effects occur.

If we look at the dose-response curve of atropine, which is the prototypic drug for all of the antimuscarinics, you can see that with small increases in dose, you have a large increase in side effects. Looking at the effects of atropine in relation to dose, we can see that at .5 milligrams, there's slight cardiac slowing, some dryness of the mouth, and inhibition of sweating. At 1 milligram, you see tachycardia, definite dryness of the mouth, and dilatation of the pupils. At 2 milligrams, there's tachycardia, palpitations, marked dryness of the mouth, and blurring of near vision, and at 5 milligrams, all of the above symptoms become marked, adding restlessness, fatigue, headache, decreased urination, and reduced intestinal peristalsis.

It's important to note that some patients might have adverse events that would prohibit them from using this medication before they achieve any benefit, while others can go up to the highest doses, achieving benefit without experiencing any side effects.

While we know that clinical trials are necessary, there are also great challenges of conducting clinical trials in children with special needs. These challenges include patient selection, consent, which children cannot give, assent, and communication. Then there are also challenges to evaluating efficacy and safety in this population.

In assessing efficacy, it's important to determine what dose provides the appropriate balance between control of drooling and adverse events. As we said earlier, the efficacy of these products is known. It's very good. But absolute xerostomia is not in the best interest of the patient.

Also, drooling can vary from hour to hour, and the assessments of efficacy must be done multiple times during the day.

What objective tools can be used to measure efficacy? The Teacher's Drooling Scale has been used in the past and is actually referenced in some of the papers that are in your packet for your information.

But then we have to discuss who would administer the tools. Will it be the caregiver who best knows the patient? Will it be the teacher who is with the patient during the day while the medicine is having most of its effect? Or will it be study personnel who may be considered more objective, or a combination of all of the three? Given this, you see that the tool that is going to be used has to be practical to be used multiple times during the day, and it also has to address the fact that there's a need to minimize interrater variability.

Assessing safety has some of the same problems. Assessment of pain and discomfort can be very difficult in this target population. In most clinical trials, self-reporting of pain and discomfort is considered the gold standard. However, patients with cognitive disability or inability to communicate cannot self-report, and failure to recognize side effects could lead to patient suffering and long-term morbidity.

Because we know that adverse events can be serious, it's very important for us to try to figure out what kind of tools can be used. Some pain scales have been developed in the past for use in noncommunicative children, and they're basically checklists of behavioral and/or physiologic characteristics, and any change from baseline is a signal that the patient is either uncomfortable or in pain. However, that signal is very nonspecific. It's hard to determine exactly what's bothering the patient.

Again, we have to ask who will administer the tool. Will it be the parent who best knows the patient and is an invaluable resource in determining whether or not the child is uncomfortable? Will it be the teacher who may be with the child while the medication is having its most effect? Or will it be study personnel or a combination of all of the above?

We've covered a lot of ground in this talk, and all of these subjects will be covered in more detail in a few moments by our speakers.

In conclusion, I'd like to say that drooling can be a serious problem in children with neurologic impairments.

Pharmacologic control appears to be effective for some patients.

There is a need for well-designed studies to provide information on dose-related safety and efficacy.

Studies must be conducted in a manner that respects the rights of the patients and results in beneficial clinical information.

At this time, Dr. Kelsey and I will take questions from the subcommittee to clarify our presentations.

DR. CHESNEY: Dr. Szefler.

DR. SZEFLER: Is there a time-of-day phenomenon that goes in terms of dosing? It sounds like this field is not well researched, and I guess as a panel we might be instructed in terms of some of the principles. Is there greater secretion nighttime versus daytime? Is there something different that might be considered in terms of dosing principles like chronopharmacology?

DR. MATHIS: Dr. Pena might actually be able to help you with the variation of drooling during the day. I imagine that during the daytime, when the child is upright, you're probably going to notice a lot more anterior drooling. However, posterior drooling goes on as well, which is what results in aspiration.

At least some of the medications seem to have their greatest efficacy approximately 2 hours after administration, but all of the agents differ.

DR. CHESNEY: Dr. Goldstein.

DR. GOLDSTEIN: As a partial response to your question, I think we've got to continue to remember that salivation is not the problem. The problem is fundamentally coordination of tongue and swallowing reflex. Even though we're looking at one approach to solving the clinical issue, we are not approaching the pathological issue at all by this approach. So, one has to be extremely careful that we realize that we're proposing to address symptoms rather than the basic pathology which raises other kinds of issues about whether there are pharmacologic approaches to addressing the basic pathological entity.

DR. CHESNEY: I have a couple of questions. I thought that was a very interesting question which raised two thoughts. One is, is there in fact increased salivation at the time of eating, and is it fair to say that most of these children will not be eating by mouth? Or they could be eating, as well as having a gastrostomy? If there's difficulty in swallowing, is it enough that they can't eat, and do you see increased salivation at the time of feeding?

DR. MATHIS: I'm not sure about increased salivation at the time of feeding, although I would imagine as a reflex that that would indeed occur.

Many of these children actually take food orally, as well as gastrostomy tubes. But many of the patients are able to swallow food, and frequently these patients, if they have behavioral therapy and they remember to constantly swallow, they can actually swallow their saliva as well. So, while they're eating and they're able to think about the process of swallowing, they can do that. It's just that throughout the day, they would constantly be having to remember to swallow, just like having to remember to breathe. So, many of them do eat.

DR. CHESNEY: Are there consistent things that can be done at night, in other words, like we do for reflux, that they don't lie flat, they lie upright. You mentioned aspiration is more likely when they're, I assume, lying flat at night. Is that pretty routine to have these children sleep in a more upright position, or are there any mechanical things? Maybe we're going to be hearing more about that, but are there things that can be done at night other than medication?

DR. MATHIS: It would seem logical to me that there are. However, I'd defer this question to the pulmonologists or other people who may be able to address this.

DR. CHESNEY: Dr. Fink.

DR. FINK: There are things that you can do at night just in terms of side position or even going to a prone sleeping. But it leads to problems with maceration because unless you continually change the padding, the kids drool all night long.

My other comment was I think in the presentation we shouldn't underestimate the significance of this problem, because it's not just cerebral palsy. There is a large group of severely retarded pediatric patients from all sorts of various brain injuries that this is a chronic, severe problem in also in terms of their management.

DR. CHESNEY: I have another question. This issue of the reaction to these drugs being such an individual phenomenon. I was impressed that you said some will have side effects before they have any effect on salivation and vice versa. So, it seems that ultimately any study is going to have to focus on the individual child's response. Is that a fair statement?

DR. MATHIS: Yes, that is. Ultimately what we would like to see happen are the tools for assessing both safety and efficacy validated and incorporated into labeling so that the caregivers could make fine tuning of the dose to control the drooling balanced against the adverse event, somewhat similar to a patient with diabetes doses their insulin.

DR. CHESNEY: So, that would be the ultimate goal in the labeling, to point out that this is a very individual phenomenon.

DR. MATHIS: Right.

DR. CHESNEY: Thank you for clarifying that for me.

Yes.

DR. KODISH: A GI question, if someone can answer for me. I know we'll hear more about the surgical solution later, but it seems like the complete cutoff of salivation and over-medicating to do a pharmacologic cutoff of salivation. Aside from the oral implications of that, are there not lower GI but esophageal, gastric, digestive function problems that would come from that? Does anybody know?

DR. FINK: I can comment on it. Constipation is already a major chronic issue in most of these patients, and typically the most clinically significant side effect is constipation, although there are stool softeners, Fibercon. There are lots of ways to deal with the constipation. That's a very obvious symptom usually.

The urinary retention is probably more bothersome because I think frequency of urinary tract infections again is frequent in this population, but something that isn't clinically evident. So, if I put a patient on one of these medicines and increase of frequency of their urinary tract problems, I am much less likely to have that reported to me than constipation.

DR. KODISH: But are there going to be worsening nutritional issues, or would that not be a problem here?

DR. PENA: From a surgical standpoint, I haven't encountered any problems with worsening nutrition.

DR. CHESNEY: Dr. Spielberg.

DR. SPIELBERG: I need some help, having forgotten some autonomic pharmacology. Anything different that can lead to new drug development with respect to cholinergic receptors in salivary glands versus elsewhere, other than trying to keep things out of CNS, such as scopolamine and things that are going to have more profound CNS effects?

And secondly, what about afferent loops that lead to salivation? The efferent is obviously acetylcholine, but the afferent loops that, for example, when you put lemon juice in the mouth that lead to salivation -- do we know what transmitters are involved in mediating those afferent loops that increase salivation? And are those potential targets?

DR. KELSEY: I don't know that I can answer your question, Dr. Spielberg, other than to say that from what I've seen in the literature, no one is using this. It hasn't been tried. So, other than that, I really can't tell you.

DR. CHESNEY: Yes, Dr. Walters.

DR. WALTERS: About a third of the children with cerebral palsy seem to have intact cognitive function. I wanted to ask are there any differences between children with intact cognitive function and those who have intellectual disabilities in terms of their ability to respond to behavioral interventions or even the magnitude of the problem of drooling?

DR. MATHIS: There actually are differences. Patients with cognitive disability can't really be taught to constantly be swallowing. I imagine Dr. Goldstein is going to cover this in more detail in a few moments.

But there are also children with very good cognitive ability who do not have the motor function to be able to swallow. Even though they can be taught and they can constantly be thinking about it, they still can't coordinate the swallow.

So, there is a difference, but it goes both ways in both segments.

DR. CHESNEY: I was intrigued by Dr. Kodish's question. What is the total volume of saliva that's made over a 24-hour period? Do we know, roughly? Because I think your question had to do with whether, say, you put out a liter and you have a liter less in the GI tract, what does that mean. Yes, Dr. Stiefel.

DR. KODISH: In titration, essentially we're titrating that volume.

DR. STIEFEL: I can somewhat address that from the literature. Most of the original physiology was done back in the 1940s and 1950s. It's somewhere between a half and 1.5 liters. So, it's extraordinarily variable in regards to that.

Things even such as concentration can affect the amount of salivary volume. Actually the responses are different in cerebral palsy versus someone with mental retardation. In mental retardation, concentration increases salivary production. So, it's a very complex issue and there's extraordinary variability.

DR. CHESNEY: Do you know the answer to the question of -- or maybe Dr. Pena does. We're getting ahead of ourselves, but since we're on the issue. Does it affect the GI tract if you cut off salivation, period?

DR. PENA: No. Generally with surgical procedures, you can't get rid of all salivation. The majority of the procedures either involve four duct ligation of the parotid Stensen's ducts and Wharton's ducts or excision of the submandibular glands with tying off the parotid ducts. You're still going to have 40 to 50 percent produce just by the minor salivary glands in the palate, the oropharynx. You cannot get rid of that. The submandibular glands produce anywhere between 30 to 70 percent of the saliva, and parotid being 10-15 percent. So, you're never going to get rid of all the saliva.

DR. CHESNEY: Thank you. Sorry for stealing your thunder.

Dr. Fink.

DR. FINK: Actually I think we do know the answer to your question directly, which is that 20 years ago, 30 years ago, in the days when the standard treatment of tracheoesophageal fistula was a spit fistula and leaving the blind pouch, those children were totally disconnected from their GI tract for periods of 3 to 4 years with no salivary or tracheal secretions reaching the GI tract, and they did just fine with tube feedings. So, mother nature may have given us the answer to that one.

DR. CHESNEY: Thank you.

Dr. Kauffman.

DR. KAUFFMAN: What's known about receptor selectivity of any of the antimuscarinics? Are they all nonselective antagonists, or are some of them more selective for the M3 than others?

DR. KELSEY: Yes, some are. I can't give you the list, but I know, for example, atropine is not particularly selective for M3, whereas glycopyrrolate is. The advantage with glycopyrrolate is that it doesn't cross the blood-brain barrier to any significant extent. So, that's one of the reasons that it's used. But there is some selectivity as far as the antimuscarinics that are available.

DR. KAUFFMAN: And a related question. What's known about how feasible it actually is to give enough glycopyrrolate to reduce salivation satisfactorily without producing the dose-related side effects? It looks to me, from what little I know about autonomic pharmacology, they're so tightly tied together, that you have a very, very narrow therapeutic window here.

DR. KELSEY: Well, it's true that there is a rather steep dose-response curve. One of the slides that Dr. Mathis showed addressed atropine, but it showed the various doses and the responses that could be expected. Unfortunately I guess for this particular question, salivation tends to be reduced by lower levels of antimuscarinics than the levels that cause reduction in gut motility, urinary retention, and so forth, but it's quite variable, and again the response is very steep.

When we get into talking about formulations, one of the things that we would expect to hear is that the concentrations of the solutions should be such that you can give very small doses in a reasonable volume of solution in order to address these kind of problems. We also would like to hear what people think about tools for assessing the adverse events in this population so that we can carefully titrate and how we can help the caregivers to titrate these doses.

DR. CHESNEY: Dr. Szefler.

DR. SZEFLER: Just one quick question. In the pulmonary world, drugs are being developed to separate out muscarinic properties. I don't know if you're aware or if even the pharmaceutical firms have thought of it, but some of these drugs that are being screened, I'm not sure in terms of their pulmonary effect and their effect on salivary mechanisms play a role. But you might keep an eye on those drugs. They're usually developed for the inhaled route, but they may have applications.

DR. CHESNEY: Thank you for addressing our questions.

Dr. Wilfond is going to talk to us about some of the ethical issues involved in titrating these medications in patients who can't always tell us whether they're in pain or suffering side effects.

DR. WILFOND: Thank you. It's a pleasure to be here. As a pulmonologist, most of the children I see with swallowing dysfunction are there because of problems of aspiration. So, for me this was a pretty obvious issue and it would be nice to have more data about this. So, I come with that bias.

The Federal regulations for human subject research have a number of criteria to assess whether a particular research study is ethical. On the slide in front of you, I listed the six main criteria. What I'll be doing is focusing on the two that are highlighted in yellow: the issue of how to balance risk with benefit and issues related to subject selection.

Additionally the pediatric regulations categorize research based upon the risks and benefits. I just wanted to point out that these types of studies would be studies that would be in the upper row of offering a prospect of direct benefit, so that we would be asking questions about whether the risks are justified by the benefits and whether that balance is favorable as the alternative, which in this case would be the lack of clinical trials.

So, when I spoke with Dr. Mathis a month ago, I said, what are the issues? Because to me, I have to admit, I initially struggled to think of what they were. She gave me some thoughts about what the issues were, which I will try to address today.

The first had to do with who decides whether drooling is severe enough to warrant a study enrollment, and might parents want intervention for their convenience rather than for the best interest of the child.

The second issue is, how can side effects be assessed in children with limited ability to communicate? So, is it possible that children would be harmed without realizing it? And might parents minimize side effects to continue the trial or just because they're unaware that there's a side effect going on?

The last issue was the equity issue. Was it appropriate to enroll children who are not in the custody of their parents? On one hand, would it be wrong to exclude them because they would be denied access to an important intervention, or would it be wrong to include them because it might take advantage of particularly vulnerable children?

So, let me give you my very quick answer to those questions, and then I'll try to give you a little more detailed answers.

With regards to the issue of whether or not this is being done for the convenience of the parents, I think it's important to point out, whether it's true or not true, which I'll get to in a moment, that that's an objection not about the research itself, but about the actual intervention. So, even if the intervention was effective clinically, that would be an objection that would be raised not by the research, but by whether it's appropriate to use this medication. As I'll describe in a moment, I don't think that's an issue.

A second point is, again, the benefits and harms of being in such a study are certainly as favorable as the alternative of using these drugs in an unstudied situation where we don't have the information about the proper dose.

The last point I'll make is that while there may not be a compelling reason to exclude people who are not in the custody of their parents from such trials, it wouldn't be a good idea to actively go out of your way to try to recruit such subjects as well.

To try to flesh it out a little bit more, let me go to the next slide. Pediatric care decisions are often made not exclusively just for the best interests of the child, and it's very common to include parental convenience and reassurance in much of pediatric care. I think as a parent we're all familiar with that practice. We also realize that short-term interests and long-term interests are very complicated.

Before I get to the medical issues, I was talking with Rick Kodish earlier this morning, and we were discussing the fact that when a family decides to move to a different geographic location, it usually causes lots of disruption for the child. It's not usually for the immediate best interest of the child, but yet parents do it. Often the hope is that in the long term it will be a good thing.

To use a more clinical example, metoclopramide for reflux. While it may be used to decrease aspiration or apnea, in less severe cases it's used because kids are puking a lot, and it is unpleasant to wash clothes very often. But I don't think we give much thought to whether that's an inappropriate thing to treat reflux in spite of the potential risks.

Again, as a pulmonologist, we use apnea monitors for reflux associated apnea. There's no evidence to suggest that the apnea monitors actually prevent any serious life-threatening events. They're really primarily used for reassurance. In fact, if we actually thought a child was having serious life-threatening events, we wouldn't send them home. We'd be trying to come up with a better solution to that problem. So, again, this is another example of providing intervention for reassurance, even though it might cause some risk as well.

My favorite one is diapers. This is purely for convenience of care. Infants do not need diapers, but it would be incredibly challenging to take care of infants without those diapers. I'm saying that sort of jokingly, but actually quite seriously in the sense that it troubles me in some ways that we look at children with disabilities in a different way and aren't willing to acknowledge that the caregivers have needs as well too, as we think about how to balance the needs of the caregiver and the child, and realize that ultimately, just as having diapers allows a parent to take better care of their child overall, I think these medications can have the same beneficial impact on children as well.

So, the other objection is there might be limitations to parental assessments. One is their ability to make an assessment about the severity of benefits or harms. Certainly it's routine to rely on parents to make observations about infants, even though we also know that well-meaning parents may not always provide accurate historical information. And we often will use objective assessments to sort this out, whether it's weighing a patient to assess dehydration, using a Ph probe for reflux, looking at apnea monitor downloads for children who are on monitors, or even with children with swallowing dysfunction, looking for evidence of aspiration to get some sense of the severity. So, I think the notion of trying to use objective tools as a component to any sort of a study is an appropriate thing, and I would certainly support that.

With regards to willingness, again most parents make very reasonable decisions with regards to their children, but we also know that some parents make very bad decisions, as evidenced by all the cases of child abuse that we see in the country. But there is no reason to assume that a person who is a caregiver but is not the parent, such as a foster parent, is any more likely to harm their child than regular parents do. So, I think that from the point of view of the question of whether or not it's appropriate to include children who are not always in the custody of their parents, from an ethical point of view, there's no reason to assume that those children will be treated any differently.

The second major point I wanted to make is the fact that because these drugs are being used without the benefits of trials, they're being exposed to harms without clear evidence of exactly how the benefits will play out. Given this lack of evidence, there would be sufficient equipoise to conduct a trial. Actually I said placebo-controlled trial, but I realize from the discussion that it sounds like the issue is really more of dose titration than just whether it works or not. So, that's probably not a correct thing to say there.

The last thing I wanted to point out was the issue of what to do for children who are not in the custody of their parents. Because this trial would be approved with the prospect of direct benefit, within the regulations themselves, there's no specific prohibitions about having children enrolled who are not in the care of their parents. There are specific provisions for wards of the state for research where there's no prospect of direct benefit and more than minimal risk. But in this case that would not apply.

Nevertheless, there's the question of should IRBs limit enrollment to children living with their parents. Again as I said, it probably is reasonable to try to avoid recruiting from more vulnerable settings, such as residential settings. It's worth noting these children would have access to these medications off trial. But in fact, most children who have swallowing dysfunction, for whatever reason, generally do live with their parents. I'm saying that not as an empirical fact from knowledge of the entire population, but just from my own experience as a clinician. The vast majority of children I see are home with their parents.

The last thing is that the scientific objectives of such a study could be met without enrolling children who do not live with their parents. So, there would be no need to do that if you didn't want to.

So, in conclusion, I think that the clinical complications of drooling are similar to those routinely addressed in children by medical and surgical interventions.

The challenges of assessing risk and benefit would be inherent in any trial of young children. Any trial with infants would raise the same questions of these assessments.

There's no reason to be more critical of parents of children with disabilities in making enrollment decisions or assessments than for other pediatric trials.

With that, I'll end.

DR. CHESNEY: Thank you very much.

Our next speaker is Dr. Maria Pena who is going to talk to us about the medical and surgical management of drooling.

DR. PENA: Good morning and thank you for allowing me to present my data.

When I talked to Dr. Mathis, what I've done -- I have an oromotor dysfunction clinic in Children's. What you're going to hear is an anecdotal experience that's been going on for about two years at Children's both in terms of the glycopyrrolate and surgical management.

I'm going to pass out what we're currently using to assess saliva management in patients, the initial interview. This comes from the Melbourne Group, the Saliva Control Group in Melbourne, Australia, as well as a rating scale chart for the parents and school people taking care of these children to assess how well we're doing in terms of the glycopyrrolate. As of yet, I don't have a compilation of the data. We're in the process of collecting it.

As we all know, drooling basically is the abnormal spilling of saliva from the mouth onto the lips, chin, the neck, and the clothing.

What we've done at Children's is basically develop an interdisciplinary approach. We have a team that consists of a speech and language pathologist, physical medicine and rehabilitation, and myself, an otolaryngologist. At times we have a pediatric dentist that participates with us. Then we evaluate these children.

That's essentially what I've just told you.

Basically management of these children can be divided into correcting situational factors and oromotor exercises. I'm not really going to talk about those, although they are addressed in the team meetings with the speech and language pathologist. In the packets that are being passed out, you have recommendations from the speech and language pathologists for some of the oromotor exercises that caregivers can participate in along with the children. The talk is basically going to be directed toward medication and a little bit of surgery.

In terms of the glycopyrrolate, as we all know, it doesn't cross the blood-brain barrier. 95 percent efficacy. That's true essentially in the 25 children that I've followed, although the reports in the literature claim that there's a lot less. And I'm going to address oral administration.

In our clinic, we've followed approximately 25 patients that we've evaluated over 2 years. Essentially we meet one afternoon a month. The patients are referred to us from pediatric specialists, from pulmonologists, other otolaryngologists, and GI.

Our patient profile. Basically our children have cerebral palsy, mental and developmental delays, and craniofacial syndromes.

The initial visit entails a comprehensive H&P from all three specialists. Basically we all come in the room at the same time and do a detailed evaluation. We also have the saliva control assessment, which we review at the end of the day because of the time limits, to get another feel for actual parent and the patient and the caregivers, if you would.

We're treating 14 patients currently with glycopyrrolate.

This is just to remind me when we initiate glycopyrrolate side effects, we go through a list of the complications, essentially dry mouth, thickened secretions, and flushing.

The urinary retention, constipation, and drug interaction. Drug interaction is an important one because a lot of these patients are on seizure medications, Depacote in particular, which we have to monitor levels because it does interact with the Robinul.

As you know, glycopyrrolate is available in chewable tablets and liquid, and it's the injectable IV solution that we're using. Because of the children's limitations, generally that's what works best for the children in terms of what form we administer it.

The IV dose, as you know, is given three to four times a day. With the oral dose, we're dosing anywhere between three to four times a day.

The ranges that we're using for the oral IV is anywhere between .04 milligram per kilogram per dose to .1 milligram per kilogram per dose. We're generally starting off with actually twice a day. Then what we have the parents and the school do is call back within a month and tell us how effective is that is. Then we increase it to three times a day and then go up a half a milligram per kilogram. We seem to be having some success with that.

Then just for the sake of completeness, the oral dose or the IV is 10 times what you would give parenterally. These are the recommendations for parenteral dosing, .004 milligram per dose to .01 milligram per dose. And remember this is Q3 to 4 hours.

So, how do we follow up the patients? This is presuming we've started them on glycopyrrolate, of course. Then we see them every 3 to 6 months, as well as the phone calls that we get from the caregivers and the school to see how they're doing in terms of the glycopyrrolate dose that we initiated. In your packets, there's a rating scale chart which we have the caregivers and the school fill out, two of the charts per week, if at all possible.

That's what I just told you. I try to have the school and the caregiver -- it allows us to pick up to see if things are really consistent in terms of the drooling. Like I said, two charts per week.

What am I looking for? I'm looking for severity and frequency of drooling and also what are the children doing when they're drooling the most.

The severity is pretty straightforward, just how many secretions are around the child. Is the child dry? Is there a mild amount, moderate amount, and severe and profuse?

The next slide has to do with the frequency. Are they drooling at all? Is it minimal? Is it occasional? Frequent and profuse and constant. Most of the patients that we deal with basically fall in this category between 4 and 6 pre-glycopyrrolate.

Of the patients we've treated, we've had actually three what I would call significant complications.

The first one is constipation. That child needed multiple disimpactions. What actually had happened is that the parent was unaware. Well, I shouldn't say she was unaware, but she didn't put 2 and 2 together that the constipation was getting worse because of the glycopyrrolate. The child understands. So, she really likes the Robinul. It really helps her socialize. I didn't find out about this until the second emergency room visit. We've titrated down the dose of the glycopyrrolate. I have to hear back from them. You're going to meet them this afternoon and they'll tell you their personal experience with glycopyrrolate and what happened.

The second child, thickened secretions. It's especially relevant because a lot of the patients I treat also have tracheotomies and that can become a potential life-threatening problem. This young lady developed much more mucus plugging. The caregiver, the nurse, was actually very savvy and realized what was going on because she was having to do multiple trach changes as opposed to the one a week that we require. We titrated down her glycopyrrolate and she seems to be doing better.

Then the last one has to do with the drug interactions and Depacote in particular. This young lady was doing quite well with the Robinul, but I check the Depacote levels once a week because we know it can interfere with the metabolism. She was having difficulty with the Depacote level. Actually we tried titrating down the Robinul. It didn't work. Then we went to scopolamine, and she seems to be doing well with that. She's the only patient where we've switched the drugs. We're due to see her in six months. We haven't had a phone call and the mother is reliable. So, that seems to be working for her.

Just to underscore the point that thickened secretions are especially important in the tracheotomy patients.

I put this slide up. This is the particular young lady. She had a sublingual mass. We did four duct ligations, tried to take out her submandibular glands. She's very retrognathic, so we couldn't do that. We tied off Wharton's duct. She still had some drooling, enough that it was causing a problem in terms of the secretions coming through the trach in particular and drooling over the lip and macerating the skin.

So, I thought it would be reasonable to go ahead and start her on the Robinul because it was a suboptimal surgical outcome. We kept titrating it up to the point where then we started having significant problems with mucus plugging. We, of course, routinely take care of the humidifier and whatnot, but dialing down the Robinul has worked.

Two of our patients failed initial glycopyrrolate therapy. The way that's determined is minimum 3 to 6 months of glycopyrrolate therapy with oromotor exercises. They have to be seen by the team, and everyone on the team has to agree that surgery is an option. Even so, I start with offering the surgical procedure where there's the least invasion, which would be the four duct ligation.

To review, surgical management, four duct ligation involves tying off Stensen's ducts and Wharton's ducts.

The next step would go on to take out the submandibular glands, along with ligation of the parotid ducts.

The third procedure is Wharton's duct relocation. Basically what you do is dissect the submandibular ducts off the floor of the mouth and insert them into the tonsillar pillars. Later on you should take out the sublingual glands. It becomes an extensive resection because these kids are predisposed to getting salivary gland cysts, ranulas, because you disturb the interruptions between the sublinguals and the submandibular glands.

Tympanic neurectomy should be up there. That entails basically lifting up the eardrum and cauterizing, cutting the Jacobson's nerve in the middle ear.

I also make a distinction between drooling and aspiration. Of those procedures, really bilateral submandibular gland excision with bilateral ligation of the parotid ducts is the only procedure you could offer to someone that's aspirating.

The last procedure I include is laryngeal diversion. I do have several patients that have ended up in the ICU in septic shock because of the aspiration pneumonias. I don't think that we'd reduced the amount of saliva produced significantly to prevent that if we just took out the submandibular glands.

So, having said that, we've had three patients go on to surgery. One patient had four duct ligation and did not improve at all. One patient had four duct ligation and improved.

Both of these patients are currently on glycopyrrolate and improved, which is an important caveat. A lot of the times, this is going to end up being combined therapy. Surgery is not going to be a "fix it" as well.

I've had to do a laryngeal diversion on one patient, and that was basically someone that ended up in septic shock multiple times, basically had consolidation of their lung from the multiple recurrent pneumonias. This child did not speak, and basically what I did was separate the airway from the esophagus. The quality of life of the child is significantly improved, no more hospitalization for pneumonias.

He's still having difficulty getting rashes. We're going to address the issue of drooling by taking out his submandibular glands and tying off his parotid ducts. Robinul has failed completely on him, and he is receiving maximal therapy at this point. Obviously, we would have done that. He really is not a candidate for oromotor exercises because of his mental status.

Like I told you, that gentleman is now scheduled for bilateral submandibular gland resection with parotid duct ligation.

DR. CHESNEY: Thank you very much.

I think we'll hear from Dr. Hays, and then we'll have questions for the last three speakers. Dr. Hays is going to discuss assessment and methods for capturing information from the patient.

DR. HAYS: Thank you. It's very nice of you to invite me to come here from Seattle. I must say when Dr. Mathis invited me to come, I mentioned to her I'm not a drooling expert. And I suppose you could take that several different ways.

(Laughter.)

DR. HAYS: But I am interested in disability related research and spend a fair amount of time with cerebral palsy patients. I thought it would be useful to talk a little bit about assessment methods. I think of it in two ways: capturing information that will be useful as outcome measure for clinical research and also gathering information for clinical care.

Let me start just briefly by talking about some of the minimum information that's probably useful in developing clinical trials for this type of an intervention for children with cerebral palsy. I think that there's a minimum database that could be useful and then a number of other outcome measures that are more or less precise in terms of their ability to capture this information.

The first is a demographic database. There's a very nice example of that was promoted by Peter Blasco. It gives some background information about every child who is likely to encounter this problem and require intervention.

Then sort of historically there are a number of different outcome measures that have been described that will help to understand the quantification of drooling and its impact of the child. I thought it would be useful to go through each one of those very briefly.

Let me go to the next one and just show you Peter Blasco's minimum database. It talks about the information that would be necessary to provide the appropriate background in entering a patient into a study to look at the control of drooling. It has to do with the basic demographic information and then a number of other issues that are related to their method of eating, their positioning, their nutritional status, dental status, medications, et cetera. This is kind of the minimum background database that would be useful in obtaining information from the patient.

The next is going back historically a little bit to talk about the quantification of drooling. Before Dr. Mathis asked me to come, I didn't know as much about drooling. I know a little bit more now. Looking back 25 years, I've learned it is possible to measure the flow of saliva and also to measure the amount of drooling by using a radioisotope. This is a study that was done more than 25 years ago in Sweden using a radioisotope assay. It involved the intravenous injection of isotope, then the extraction of saliva from the mouth, and the weighing of bibs and running them through a scintillation counter. It's a very accurate, precise way of measuring saliva flow. But as Janet Camp-Bruno has suggested, the actual measurement of saliva flow is quite possible but, in fact, probably irrelevant in these types of studies.

The next is a Canadian study that looked at the actual quantification of drooling, not so much saliva flow, but actual drooling. This was done by two bioengineers who I think liked making little devices. So, they devised a cup/bonnet collection method with a vacuum extraction pump and a collection chamber. They devised a way to collect data every 15 minutes at least 10 times a day and were very accurate at quantitating drooling. Again, very accurate, very useful for the quantification of drooling, but it has very little relevance to the patient.

The Teacher Drooling Scale you've read about in the information that's been provided for you. I think this is again probably one of the most useful tools, and it is less precise but I think more patient friendly and probably is a little bit better at describing the actual impact of the problem for the individual patient. It's a five-point scale and information can be collected by a parent, a caregiver, a teacher, and it is most useful if it's done in a standardized fashion.

A much more precise way, but again much more labor intensive, is the next which is time sampling. If you're familiar with this type of research, time sampling usually requires an enthusiastic graduate student who is willing to have a metronome in his or her ear and then will actually measure behavior on 20- or 30-second intervals and do it over 40 data points per session. Also, this is a time sampling technique that was again used by Janet Camp-Bruno and is very useful, but again extremely labor intensive and expensive.

Behavioral and Medical Rating Scale. This is kind of an adjunctive measurement tool that can be used to add in the additional information that you get after you quantitate drooling or have some idea about the actual amount of the problem. It is not a substitute for a careful investigation or access of adverse events, but it can provide sort of day-to-day, hour-to-hour information about what's happening in conjunction with the intervention and the use of the medication.

A parent report questionnaire has been used by Peter Blasco and his group very effectively I think. Again, it requires some thought in the development of the questions that are provided, but it's a good example of the fact I think that parents are probably the most likely to be able to accurately identify the effects of the treatment and are going to be most probably relevantly committed to the outcome of the patient.

So, the four important domains that should be present in a parent questionnaire are, of course, the use of the medication because it can be quite variable. Parents need to be given very specific guidelines about understanding and reporting side effects. The Teacher's Drooling Scale can be used in a parent questionnaire just as well as it can be in a more institutional setting. And there has to be information about the discontinuation of medications, the reasons for that, and the possible adverse events that are associated with those.

Let me talk a little bit about a tool that has not been used to this date in the evaluation of drooling and it may be useful. This is goal attainment scaling. Goal attainment scaling is becoming I think more and more popular in disability and related research because it not only talks about the effect of the intervention, but also the value of that intervention on the individual patient. As we become more aware of the effect versus benefit aspect of doing disability research, I think we're interested in not only documenting that your intervention has an effect, but also that it has some relevance to the individual patient. I think ethically, as I'm sure our ethics consultants can tell us, that relevance is best described by the patient or the person who is best able to describe the best interests of that patient.

Goal attainment scaling allows a patient or a parent to identify at the outset what they would prefer to have happen as a result of the intervention. It gives them an opportunity to identify their own goals. Then through a series of questionnaires over the course of the intervention, they're allowed to explore whether or not the treatment has actually helped them to accomplish these goals. It also has a part built into it so that you can attach value to the goals so that there's a minus 2 to plus 2 rating scale that helps you to understand whether or not, if there are a number of different competing and compelling issues, those that are most important to the patients were the ones that were actually the outcome of the intervention. So, goal attainment scaling is an attempt to increase the understanding of the benefit to the patient, as well as the effect on the patient.

Then this is the last thing I want to share with you. I think what you're hoping for me to say is that this is the way that we can communicate with a nonverbal patient and get an idea about what adverse events are. I don't really have an easy answer to that question. Very briefly, I think especially in the pain literature, if you look at the work of Donna Wong and Mo Pomietto and people like that, there are a number of relatively crude analog based scales that will help you to assess pain in a nonverbal patient. But I think that getting this information is not necessarily easy and doesn't lend itself very well to quantitative analysis.

However, I think that it's probably safe to say that the person who is best able to represent the best interests of the child, the person who is probably best and most invested in the intervention and in having accurate information about the child is the parent, is the family member.

Let me just briefly take you through this communication tool that we've begun to use with I think some intriguing results in some of our studies.

We call it the decision-making and communication tool. It's based on the Johnson, Siegler, Winslade method of ethics case analysis. Some of you who are familiar with that little primer about clinical ethics are familiar with this idea.

But the purpose of this tool is to take history taking and information gathering and break it down into its parts. We talk about a four-box method here.

The sort of northwest corner, called medical indications, is where we capture information about the actual physiologic effect of an intervention. We also use that box in the communication to give the family information about what to expect from this drug, what to expect from this treatment, what are the risks, what are the benefits, that sort of thing.

The sort of northeast corner there is called patient preference. This is where it's pretty much a reminder for the clinician to find out what the patient really wants, which sometimes can get lost. It helps us to understand whether or not this intervention is really going to be relevant to this individual patient. So, it forces you to take some time to find out whether or not the patient really wants this intervention, what their expectations really are.

The sort of southeast corner is called contextual issues. Contextual issues is something that also needs to be included in any kind of clinical research and is often not paid enough attention. What is the context in which this intervention is going to be played out? Is this a child who is in school, who is not in school? Is this an adult? Does drooling affect his interactions in a social realm? Does he have a social life? Does he have a vocation? So, the context helps to fill out some of the background of where this treatment is going to affect this person's life.

Quality of life is where we allow the patient or the person who can speak in the best interests of that patient to determine whether or not this treatment has really affected this patient's quality of life. This is not an easily quantitative tool, but it's very, very useful, we find, in improving both patient and provider satisfaction. I think it helps us to be able to capture again, as I said before, the effect and the benefit of the intervention. We'd like to be able to use this to a greater extent in clinical research around disabilities.

Thanks.

DR. CHESNEY: Thank you very much.

Questions for Dr. Wilfond, Dr. Pena, and Dr. Hays. Dr. Danford.

DR. DANFORD: It seems to me we could make our investigation a great deal easier if we could select only those patients who have sufficient cognitive and communicative skills to let us know about the response to the medicine and the side effects reliably. But I have some worries about that.

The first is availability of such patients. Does drooling occur sufficiently frequently in patients who have communicative skills to allow a sufficient population to be available for study?

Secondly, are communicative patients with drooling representative of the population as a whole?

And third, is it ethically sound to selectively subject these patients to the risks and benefits of the research?

DR. WILFOND: In your last question, you were referring to selecting which patients?

DR. DANFORD: The ones with the highest communicative skills.

DR. WILFOND: I think my short response to all three questions is that a majority of the patients who have swallowing dysfunction who have significant problems drooling are able to communicate. As a way of treating those patients, we also need to be able to develop the skills of assessing them in a clinical setting as well. So, my concern would be if research was only done in patients who could communicate, we still would be lacking some of the information that we would need to make those clinical assessments of the children. So, for that reason, I think it would make sense to do the research in that broad population.

DR. CHESNEY: Dr. Nelson had a question.

DR. NELSON: I'm struck by the comment that Dr. Pena made about dialing down the drugs. I have sort of two questions which are related.

In doing that, did you feel or did the families feel that they were accepting a certain level of drooling that they otherwise would find unacceptable simply to avoid undesirable side effects so that the real question is finding that rather narrow therapeutic window between effect and side effect?

And then the research design question comes in. I'm not that concerned about limiting this to individuals who can self-report since there's a lot we do in pediatrics for a lot of kids that can't self-report what's going on. But then the question arises in my mind of whether there needs to be blinding as part of that assessment in a research setting, not so much between groups, but certainly given this more physiologic endpoint in a sort of randomized, crossover, blinded individual as their own control kind of study.

I wonder if you could comment on both those points.

DR. PENA: To the first question, when you meet the parents and the family, the child, they want no drooling. I can't tell you the number of times: Can you increase it? Can you increase it? They want no drooling. As long as they're not having any side effects, I'm willing to do it slowly and in increments.

But what happens is this very situation. That's why I asked them to speak to you all. They are not going to report or won't think that the complication is secondary to the glycopyrrolate.

But the children really want to stop drooling because it really makes a significant impact on their life. So, they ask me can they still stay on the glycopyrrolate. And what I've done -- and I admit it; it's two anecdotal experiences -- is go down to the dose I knew they were doing okay with and still having some drooling and basically following them out and see how they're doing. With the two patients I've had that problem, we still haven't had 3 to 6 months' follow-up to give you a good answer.

But, yes, it's certainly a problem. Even though I try to safeguard it by having all the questionnaires and having the caregiver, as well as the school, report it to make sure that the responses are as consistent as they can be from as many people observing the children, there are going to be problems.

In terms of your second question, I'm sorry.

DR. NELSON: It was a question about the importance of blinding in making those assessments. I'm also struck. What's unusual here, when we try to pick the right dose, is there seems to be physiologic variability, but here there will also be, relative to the last presentation, variability in the judgment on the part of a parent of where the drooling is acceptably controlled and the side effects are acceptable. So, we're not so much picking an endpoint where there's efficacy and safety. We're picking an endpoint where there's enough efficacy and not that much side effects. So, it's almost a different endpoint than our normal clinical trials. But the point is blinding in that assessment to know that we're getting data that's not influenced by the bias about the medication.

DR. PENA: Well, I agree but I don't know how we go about doing it.

DR. NELSON: Well, you could simply spend 2 weeks on a blinded medication, 2 weeks on the other part, so just do a sort of dummy back and forth so that with blinded assessments, you begin to find is where is that child's balance and do it over enough kids that you can begin to draw some conclusions, rather than just using the medication and then randomize between groups because I think it would be hard to justify leaving a kid on a placebo to get that.

But I don't think it's so much from the standpoint of efficacy as it is from knowing that you have a fair evaluation of the endpoints, particularly if you're using, which I agree would be more useful, the drooling scales, the BMRS, the parent report questionnaire, goal attainment scaling, all of which I assume would be impacted by the bias of the observer fairly significantly.

DR. PENA: I think it's a good point. I suppose we could do it longer. Two weeks is really not going to work on and off. I mean, there's reality. They're not going to do it. It's not going to happen. They'll know right away, especially if they have some improvement, and they'll say, what's up? And 2 weeks later they're drooling again. You can tell within 2 to 3 hours for most of these patients that they're significantly improved.

So, you're going to have two problems. One, they're going to fall out of the study because they're going to get discouraged and think it doesn't work. Then you have the next problem. The glycopyrrolate actually did help them and they don't want to participate anymore, which has happened to two people that we have in the study.

These patients are very complicated. The care of the patient, the multiple, multiple levels. I don't know. I don't see in reality how it's going to work unless we take 10 isolated and put it together, but can you extrapolate from 10 patients and which 10 patients would they be?

DR. CHESNEY: I think that's one of the issues we probably need to address.

I have a question about the pharmacokinetics of these drugs. Would it be more beneficial or has anybody looked at the issue of giving it more frequently so that one maintains continuous levels that are effective? Is there a phenomenon of it takes a couple of hours to get an effect and then you have a maximal effect for a couple of hours and then the salivation starts again? Has consideration ever been given to giving it more often and maintaining maybe not such a high dose?

Dr. Fink.

DR. FINK: I think obviously a continuous drug would be better because with limited experience, I've used scopolamine patches, and in the patients who don't get neurologic side effects from the scopolamine patches, which gives you 2 to 3 days at a time, it works wonderfully. But unfortunately, scopolamine is the wrong drug for a lot of patients. But there's no question something like a long-term patch that gives you 2 to 3 days of continuous efficacy probably has better biologic effectiveness.

DR. CHESNEY: Yes, Dr. Walters.

DR. WALTERS: I have a question for Dr. Wilfond about selection of subjects in this research. I think you made a very good point about institutionalized patients or residential patients not being ideal as the first subjects in such a study. I wonder if you would draw a similar distinction between children who are living with their long-term parents and children who are living with foster parents. I don't want to stereotype foster parents. I do think that there is a difference in the level of commitment of parents who plan to hang with their children on a long-term basis.

DR. FINK: Not on the ethical part of this, but I think there's a real problem with that conceptually which is, if you actually look at the impact of drooling, drooling is one of the primary things that can lead to institutionalization of many kids because it increases the care needs so dramatically. So, if you rule out the institutionalized patient with drooling, you're taking the mildest group or the most competent parents, and that's a big bias in and of itself.

DR. WILFOND: There are actually two issues. One is the issue of the institutionalized patient and the patient in foster care. Maybe I'll first respond to Bob and then to Leroy.

I think you raise a good point, that it's perhaps a different population, those children that are institutionalized versus those that are not. But unlike the communication issue, I guess my initial assumption, which I would need to clarify, would be that the population of non-institutionalized patients is probably broad enough that you could still learn a lot of the information that you need to learn without going to that group, whereas I would be much more concerned about restricting it to patients who were able to communicate and that group being more skewed way to the other end.

With regards to the foster parents, I think it also varies from state to state as far as what foster parents are allowed to do legally. I really can't speak directly to that. I'm not cognizant of all those issues. But from an ethical point of view, I think that foster parents are as likely to be as committed to their children as other parents would be. I'm partly saying that just from my own experience of dealing with foster parents of children with disabilities. They're often in many ways more committed than the broad range of parents. So, I would actually be comfortable with the types of assessments and observations they make. Generally, when I'm thinking about clinical decisions I make with foster parents, they're usually quite capable of balancing risks and benefits.

DR. CHESNEY: Ms. Woerly.

MS. WOERLY: My group that I work with are medical foster, and these parents are very committed to taking are of these children. They know what they need. They know what medications they need. They can go into a clinic and tell the doctors what exactly that they're looking for. They have the kids that are drooling. They know the problems that it causes.

The only problem is that the state will not allow these children to be used as research subjects. That's the biggest problem, but they would be the best ones. They are the caring people. They're really in tune and that's they're job.

DR. WILFOND: They're not prohibited by the research regulations from participating. It's just that the organization in terms of foster care makes that judgment even though we could say that's perhaps a wrong judgment for them to make.

MS. WOERLY: Right, exactly.

DR. CHESNEY: Dr. Kodish.

DR. KODISH: Ben, I thought your talk was very nice, but one area that I thought was missing that's important to talk about is assent. I think it needs to be said that purely from an ethical perspective, it would be preferable to enroll children who are capable of some degree of assent. The more, the better in the same way that traditionally we've thought it's better to experiment on adults over children.

Having said that, there are times when the needs of good science and good ethics clash. While it might be ethically preferable to conduct these studies with children capable of assent, I don't think we ought to prohibit, if the needs of science are such, research on children who are completely incapable of assent given that we have caring parents who are hopefully making good best-interest decisions.

DR. CHESNEY: Dr. Goldstein.

DR. GOLDSTEIN: I think we've got to recognize that we're dealing with a very special subset of children. These children rarely have isolated drooling. They are at the end of the scale where they have multiple impairments and multiple disabilities, and communication is often associated with this.

So, if we try to find the pure subject, given that there may be as many as 10,000 children in the nation where drooling is a meaningful problem, if we try to subset that into children who can communicate or children who are not in some kind of institutional setting because of the multiple impairments and the multiple disabilities, the scatter around the country are going to make a coherent trial extraordinarily difficult to operate in order to get reliable data with enough numbers in the numerator and denominator to give any important tests of significance.

I think all the issues that have been raised are pertinent issues that need to be considered, but I would again urge the committee to consider that this is a group of children with very multiple impairments and disabilities, of relatively small numbers -- relatively -- with many, many characteristics. So, if we start developing cells as to which kind of child with which kind of drooling is beneficial by any particular impact, we're going to find ourselves in a terrible numbers crunch in order to develop tests of significance.

I would like to, if I may, address the issue of blinding. I'm reminded of the old biostatistical joke that if you have a supposed treatment for active rabies and you give it to one person and the person recovers, it's a miracle. If you give it to two people and they both recover, it's a trial.

When the endpoint is absolute and the natural history is well known, you really don't have to blind even though blinding is a beautiful gold standard to attempt to approach, but it isn't necessarily the law of the Medes and Persians. So, one can blind observers in the sense that more than one observer makes the evaluation and tests the reliability of the observers without necessarily blinding the application of the intervention.

The only reason I bring this up is again to my original point. We're dealing with a relatively small cohort of children with multiple, multiple problems. These problems are going to affect the impact of the medication because they do have upper motor neuron lesions primarily. They have all of the characteristics of upper motor neuron lesions, and they're a very tough group of kids with many, many problems.

DR. CHESNEY: Thank you.

Any other questions for our speakers? Dr. Fink.

DR. FINK: More a question I guess maybe going back to Dr. Kelsey. It would seem to me that this discussion, since we're talking about drugs that are already licensed for this indication in adults, that we really do not need to talk about an efficacy trial in pediatrics, and we're really going to be talking about pharmacokinetics and dosing, safety and side effects, in which case blinding really shouldn't be much of an issue.

DR. KELSEY: Yes, I would agree with that. We're looking at efficacy in the context of the adverse events, the risk-benefit ratio.

One trial design that we have seen employs a placebo control. What was done in this proposal is that the patients were titrated by their caregivers over a period of weeks to what they considered to be an optimal level based on the side effects. They would basically increase the dose until the side effects became intolerable and then dropped down. Then once a dose had been established for that patient, then they were randomized to either placebo or drug. We're not particularly wild about that design, but that's one that we've seen where you could use a blinded design. It would be different than the crossover that was proposed earlier.

But to answer your question, we're really interested in efficacy only in terms of the risk-benefit ratio.

DR. FINK: This is a drug or a class of compounds where we're willing to extrapolate the adult effect to pediatrics, and there's really no reason, unlike yesterday, to question whether the pediatric effects would be markedly different in terms of efficacy.

DR. KELSEY: We believe that these antimuscarinics work in kids. The doses may be different, but the effect is the same.

DR. CHESNEY: I'd like to go ahead. Could we save that for our discussion later?

DR. NELSON: Yes.

DR. CHESNEY: Thank you.

Our next speaker is Dr. Scott Stiefel to give us the perspective of the American Academy of Pediatrics.

DR. STIEFEL: Greetings from Utah. I both recognize and appreciate the privilege to address this committee today.

I probably need to talk about my biases. Being a pediatrician and adult psychiatrist and been involved in the care for the last 10 years of only kids with developmental disabilities and also being probably about the only person in the country who is both on the clinical research side of the university but also the medical director for a state human services agency, what you're going to hear today is a reflection of that broad range of biases.

I've also been given a dual charge: one, to talk about what the American Academy of Pediatrics' Committee on Children with Disabilities thinks in regards to drug studies in general and particularly in regards to these issues, and also to share some clinical experience in regards to what is really going on with this population, which I think continues to come up as one of the major issues.

The big picture is that we strongly support meaningful studies of all medications used in children, particularly those vulnerable children with special needs. I think it's absolutely critical to realize that indications in kids without special needs are not always applicable to children with disabilities. So, to add another layer, we have to look at not only just indications in children, but indications in the appropriate groups.

In general, the studies must address all the things that we've talked about. But I want to add one new concept, that adverse effects must be presented in children in a developmental context, and I'll talk more about that in the future.

Again, I think what we're talking about is not efficacy studies, but we're talking about a paradigm shift that must be made in terms of how we look at the study of these medications. That's partly why I came here today because this is a great microcosm to be able to extend to not only this issue, but all medication studies in children with special needs.

What is critical is to look at some subgroup differential response. In this population, look at issues of polypharmacy.

Also to make choices between medications in the same class. We don't study that and we have to start studying those things.

Then again, how do we make choices between different therapies? The literature does not help us with this to a very great extent.

The multiple ethical issues have already been explained and I'm not going to go into those.

This topic also presents an unusual and complex set of issues. Again, what we're talking about is a Zen-like balance that must exist between inhibition of saliva production and adverse effects, again realizing that saliva production is not the major issue in terms of rate. Our literature clearly, in terms of critical review, lacks scientific rigor and provides little comparison between these different interventions. These children have complex pathological and adaptive functional assessment, and their needs are very complex. There are many etiologies and mechanisms which create the subgroups.

Even though some have been presented, we have no truly quantifiable measurement techniques. That has been pretty well talked about, so I'll move on. But there also exists I think in the literature regarding this a general pessimism about pharmacological management. In your references, I've also put articles in that are more optimistic towards pharmacological management.

Again, all the things that people have said before, but what is clearly important is polypharmacy in this population. We're going to talk a lot about it.

Now, you open any pharm textbook, anything else, this is the anecdotal information that exists. Infants and young children are especially susceptible to toxic effects of these medications. There's a need for close supervision of infants and children with CP and other forms of brain damage when giving these medications. And increased response to anticholinergics has consistently been reported in children with disabilities, again with the dosage adjustments that we've been talking about. This is anecdotal, folks, though, and we have to look at where this came from.

Again, I think we have to also not just study these medications, but understand the whole spectrum of things that lead to this, which include speech problems, feeding and swallowing difficulties, structural and motor problems, upper respiratory congestion, and of course aspiration at one end of the extreme.

What we have to do, when we're assessing etiology, is we really have to look at all these different things. Again, this drug has action only on rate of saliva secretion. So, again, there are a lot of things that go into it, the cognitive appreciation of the salivary spill and all the other things that folks have talked about.

Therapies also have to be hierarchical in nature, in other words, with the least invasive first, everything from behavior modification to surgery. I think you brought up a critical point that's not established in the literature, which is that many times multiple things have to be used at the same time.

The epidemiology we know. As you can see, 10 to 30 percent is a broad range in regards to drooling problems in cerebral palsy, but I also appreciate the fact that other people have talked about that we're not just talking about cerebral palsy. In fact, we're talking about a broad range of kids. We see a mixed population which is very unusual to see everything from birth to death. We've been doing the medical home model for over 10 years in terms of coordinating mental health and pediatric care and habilitative services for these folks. Again, we don't have a clue what the percentage of drooling is in severe, profound, and moderate mental retardation. We just don't have any help in the literature.

This might not be popular, but the reality is that the gap between incidence and prevalence in developmental disabilities is closing. What this means is that we're saving more of these kids and the numbers are actually increasing. The complexity of these children is also increasing dramatically as is the life span, which brings other issues into this. Again, the expectations of children that are now living and being integrated into our communities and schools are also increasing.

These are the kids we actually are talking about. I really want to talk about that. These kids have central nervous system developmental problems or damage that translates into a developmental disability or mental retardation. In addition, almost all the kids we see have other chronic central nervous system illness such as cerebral palsy, epilepsy, movement disorders. All these kids pretty much have multiple chronic general medical illnesses. Most of these kids have sensory and communication challenges. There's a new field of comorbid mental illness in this population which also needs to be looked at. It has significant impact. And many of these kids also have severe behavior problems. This is actually the population we're going to be studying, folks, and I think the comments about trying to just choose folks who have no communication problems and no cognitive disability are very appropriate. Obviously, our recommendations are that you can't do that.

These kids have fragile brains.

The average kid in our clinic, unfortunately, comes to us -- we're the bottom of the drain -- on six to eight medications which have central nervous system activity. Polypharmacy is horrendous. Two to four of these medications, depending on which subgroup we're looking at, have additive anticholinergic activity, and we're talking about adding a third or fourth medication to that. 70 percent of the kids have behavior problems that are the mode of presentation, and they have two or more medical problems that have not been recognized or appropriately treated that add to their behavioral presentation. In our population, which is about 2,500 kids and adults, about 1.5 to about 5 percent, depending upon the subgroup, are on drooling medications.

I don't want to go over this, but I want to point out a couple of things that we're beginning to see emerge.

First of all, the gastrointestinal comments I think are clear. The only meaningful thing I do in my life is treat constipation. It's the one thing that makes more difference than just about anything else I do.

(Laughter.)

DR. STIEFEL: The other thing we're beginning to see is a tremendous worsening of gastroesophageal reflux, which is a problem in this population. We know that these medications have effect on the sphincter and other sorts of things, so the physiology also is correct.

The other thing is that most of these kids -- and a lot of them have severe pulmonary problems. Again, it's a very complex sort of chain of events and vicious cycle that you get into with these kids.

The other problems that we're beginning to see, as we're starting to study sleep disorders in kids with disabilities, are that none of these kids have normal regulation and architecture, and these medications can further affect sleep regulation. It's a major, major issue.

Then the last thing is my bias is you can't separate the brain out into central nervous system and psychiatric problems, general medical problems, but there are tremendous psychiatric implications of these medications.

How can we look at adverse effects? Well, again, what you have to remember is that adverse effects in this population are going to mostly manifest as behavior changes, particularly in a limited verbal status.

Assessment must first provide an understanding of the child's learning strategies and degree of cognitive disability. If we don't understand how the kid experiences the world, we can't study him.

We then have to establish a relationship with that child and the family and a shared communication strategy with that child. That doesn't have to be verbal. There are many ways to communicate with kids.

We also have to objectively be able to assess pain and discomfort, and that's been well presented.

This is the other kicker. All the diseases that were on that last slide don't show up in 2 weeks. These are things that take sometimes months and years to ramp up, and then after they've ramped up, they take sometimes months and years for the parents or caregivers to recognize that it's a problem. So, it's a real challenge in regards to seeing these folks. I introduce the concept of these disease cycles that we get into. These studies are going to have to be of significant length using outcomes tools to be able to look at these issues, if that's really what our charge is.

Behavior. How do we quantitatively assess it? Well, you've had some tools, and I'll give you some more. But remember all symptoms usually are behavior changes. Behavior is usually the symptom when the child is having pain or discomfort, having many times symptoms of general medical conditions, many times symptoms of mental illness, and again many times symptoms of iatrogenic side effects.

In these kids, you have to have a multi-disciplinary or interdisciplinary, whatever word we're using this month, assessment --

(Laughter.)

DR. STIEFEL: -- that includes medical evaluation, developmental analysis, a functional analysis of behavior which is a scientific tool that we use, and then a use of many of the rating scales that we use to provide both data for assessment and evidence of change and tracking.

I've already made this point. It should be obvious at this point in the history.

Safe and ethical conduct. Well, this is a vulnerable population. It is our responsibility to protect. The point I want to make is part of that responsibility is demanding meaningful studies, which is what we're doing.

The need for multidisciplinary team assessment. I keep saying that. That means it must be important. I'm a little bit perseverative to those who know and love me, but it is an important thing. You can't do this without the expertise and without understanding this population.

We also need agreement in terms of forming the database for description of etiology, pathology, and subgroups. Not that we're going to necessarily separate the subgroups in terms of studying them, but we have to actually know what the other issues are and what the other interventions are. We have to look at, somewhere down the road, subgroup response patterns so that we can get into making more meaningful recommendations as to when these drugs can be used. And then we must study, again, the etiologies.

I already talked about the increase in length of time. I'm saying it again. You can't do this over the short term.

The other thing is that in the literature there is some talk that some of these medications can also form tolerance issues, and we're going to have to look at significant length of time. You know, the brain and the body up and down-regulate things in response to what's done. So, we have to look at that in terms of discontinuation, whether that's tolerance or whether there are other things that go into that.

We have to establish and support and promote research in the consortiums that look at these issues, and then again all the other ethical issues that go with this.

I agree with comments that were made earlier about IRBs, but we must also include state and local disability human services rights oversight. We cannot look at those boundaries that many times are imposed and not address that. We have to look at that and we have to start to involve those folks. In all of our studies, we actually involve those. That's partly why I'm the medical director for the human services agency, so we can get away with it.

(Laughter.)

DR. STIEFEL: It's critical I think that we use independent assessors. That doesn't mean not use the caregivers, but we clearly have to use independent assessors also, to come back to some of your questions. And we can address that later.

The other part that's always missed in kids with disabilities is that you have to always include the child, adolescent, or young adult regardless of their cognitive disability, regardless of their cognitive strategy. There hasn't been one kid I've ever taken care of that I can't develop a relationship with and get information from. You have to include the kids in this.

We need consensus definition and assessment in regards to the significance of the impairment -- and that's been talked about -- and the etiology.

Quantification of volumes. There are a lot of systems out there. The newest is Chin Dry System which is going to come out of the Texas folks. But again, that's only one small part of the problem, and again, this is a very complex issue.

We also need consensus as to the degree of impairment caused by drooling. That's one thing about which we still have huge issues getting consensus as to what is the degree of drooling. The reality is it's a different thing for each kid and a different thing for each family, and that's really where the challenge is.

I also believe that we must identify medications with good efficacy and good side effect/benefit ratios. That's, of course, a summary statement.

Again, more support for studies that are broader range, more meaningful in terms of the drug choices and polypharmacy.

My recommendations and our recommendations for formulations. Many of these kids have swallowing difficulties, of course. Oral forms are an issue there. Whether or not you realize it, giving a medication five times a day is extraordinarily disruptive to a child's life and a family's life. So, we have to think about those kind of things.

Transdermal. I hospitalized three kids last year after taking Catapres patches. These kids put things in their mouths and they chew them. So, we have to look at transdermal applications and the safety issues.

Pharmacokinetics. Of course, we have to do pharmacokinetics. We know kids are not little adults. We have to do it.

Things like quaternary amines, glycopyrrolate, that we look at, only have absorption of 25 percent. So, huge issues in regards to these issues.

The blood-brain barrier. There's a very interesting part of research right now. What you will recognize is that a lot of these kids with the severe CNS problems they have, though, have ongoing insults and variable intactness of their blood-brain barriers. That's true in hydrocephalus, kids with chronic epilepsy, immune disorders, self-injurious behavior, and other sorts of traumatic brain injuries. We're talking about using drugs like glycopyrrolate that don't cross a blood-brain barrier. I'm making the point that these kids' blood-brain barriers are variable.

We also -- again, just to punctuate -- need broad titration and dosage latitude. Again, I really applaud this committee. We're not going to address this retrospectively. We're going to do it on the front end.

Medications should not be extemporaneously formulated.

Again, polypharmacy sort of raises its head in this group.

Again, guidance in dosing, other issues. I believe that we have to have discussion of adverse events, the additive polypharmacy, the general medical and psychiatric problems that can lead to recognition of adverse events, and again the titration schedule.

Other therapies must probably be looked at because it's not all commonly known in the people who will use these medications. Not that we will make recommendations, but that discussion needs to occur in the literature that we provide with these medications.

I am going to make a strong statement, though, that dental recommendations actually need to be made for these kids. When we cut down saliva production, we have to not only do prevention, but we also have to do recommendations for surveillance and intervention. The caries in these kids and the dental care just become quite profound sometimes. Again, that's a longer term cycle that we have to look at.

Then I'm also going to challenge you that all of us physician types are now using electronic management software for medication interactions and other sorts of things. I would encourage interface between FDA and some of the people who are putting these kinds of things out as a way to actually look at the polypharmacy.

Other issues? Thank you.

DR. CHESNEY: Thank you very much.

Our next speaker is Dr. Murray Goldstein who is going to give us an overview of the scope of the problem.

DR. GOLDSTEIN: I've been asked to address the problem from the perspective of a family based organization, United Cerebral Palsy. Within the organization, there is a second organization known as the Research Foundation in which we attempt to address the biomedical issues relevant to developmental brain injury, specifically cerebral palsy.

To repeat some of the numbers that you've already heard, the best estimates at the moment are that there are about 500,000 persons in the United States with the syndrome referred to as cerebral palsy. These are fairly loose and thin data because cerebral palsy is not a reportable disorder. We don't have Framinghams and Tecumsehs to help us. However, when we do extrapolate from the Scandinavian data, they are so remarkably similar to our own experience that, extrapolating from that, we still come up with about 500,000 persons in the United States.

We also are reasonably comfortable that of the 500,000, about 200,000 are under the age of 20. So, we're dealing with a population which is characteristic both at the children side and at the adult side. Of these 200,000, it is estimated that there are about 20,000 with significant problems of drooling that does interfere with quality of life.

Will this population grow? Well, it is growing. Within a decade, we have gone from an incidence rate of 2 per 1,000 live births to 2.8 per 1,000 live births, and it looks as if those numbers are steadily increasing.

Why are they increasing? The wonders of neonatology. The low birth weight infant now of 1,000 grams has a reasonable probability of surviving. The infant of 1,500 grams will certainly survive, and about 30 percent of these infants do have developmental brain damage right in the neonatal nursery. So, we're facing into an ever-growing problem that will affect us both not only medically but as these children enter the school system and in later years into the work place. So, we can look forward to that.

Secondly, the wonders of the ability now to have infertile relationships become fertile, and we do know that this usually results in multiple births, again a major risk factor for developmental brain damage.

So, on each end of the spectrum -- the very small infant, the mother with more than one fetus -- we can predict that this problem is going to get worse. So, we have to look forward to the issue of how do we intervene as a society to address these problems and particularly in that cohort of multiple disabilities.

As physicians we too often look at the issue of impairments. We like physiologic measurements. It's easy to tangle with and we grow up in the world of impairments. But parents don't think of impairments. They are not really, really concerned with spasticity; they're concerned immobility. They're concerned with drooling; they're not concerned primarily with whether the ducts are working properly. So, disability becomes a major, major factor when you look at it from the parental or caregiver's viewpoint, and certainly as these children develop their own personalities, they are also concerned with their disabilities and not their impairments, which is why the World Health Organization, the National Center for Medical Rehabilitation Research have come up with these patterns of being able to describe this complexity of interactions.

A point that I did try to make in response to one question is we are dealing with a population of multiple disabilities. It is relatively rare that we're looking at a child whose only major problem is salivation. Well, salivation is not the problem; it's drooling. Thank God they're salivating, given the problems that would be associated with the lack of salivation. So, we're dealing with a small cohort of children with multiple disabilities, and it becomes a technological tour de force to put this population together and come up with meaningful numbers so that we can get some sense of statistical significance about the importance of any intervention.

Thirdly, whether we like it or not, these studies are going on all over the country. They're going on in physicians' offices, in clinics all the time with very biased populations and with very biased observers. They're trying to do their clinical job, and doing it well, but they recognize full well the population they're seeing does not represent the population of droolers, and their approaches don't necessarily represent the population of different approaches.

So, for the benefit of these children and of their parents, the caregivers, we must approach it from a national viewpoint with a trial because in addition to the trial and the specific data we will get addressing the question, we're going to be able to begin to address this population and its characteristics if the population is broad enough and big enough. And only through a national effort can we do this.

Finally, my plea to the FDA is I recognize your responsibilities as a regulatory agency. On the other hand, close collaboration and cooperation with other government and nongovernment agencies is imperative. As you know, a new national center for birth defects and developmental disabilities has just been put into place by law, and now with an acting director, in the Centers for Disease Control. It has a $60 million budget. Those of us who are working on the Hill will see that that will double in the reasonably near future. Here's an agency whose responsibilities overlap tremendously with yours because they will be the data-gathering agency. The NIH, obviously, in terms of the pharmacologic and physiologic approaches to these issues.

My plea is has the time come to recognize in a positive way the overlapping responsibilities of the several agencies so that we can, in fact, work together to begin to identify some of these problems and, working together, address them rather than being forced into our own little cubbyholes?

I had the privilege years ago of being an Assistant Surgeon General and working with Dr. Koop. I can tell you our conversations about this were wonderful because Dr. Koop refused to recognize that there were agencies in the Public Health Service. He felt that there were physicians and scientists who had an opportunity and that the agency role was perhaps inhibitive.

Finally, I urge you to incorporate the use of the parents even though they are obviously biased. Thank God they're biased. On the other hand, I have learned by working with them that they are often the most scrupulous observers of what is happening to their children, and the rest of us who plug in every now and then and take a look and plug out again don't really understand the natural history of what's going on with that child in its day-to-day involvement and interaction. So, parents are superb observers. Sometimes they scare the hell out of me with the conclusions they come to, but they're good observers.

(Laughter.)

DR. GOLDSTEIN: So, in the observational ascertainment of an intervention, parents need to be one part -- not the part, but one part -- of the observational data-gathering. And that's where the blinding comes in rather than the children.

Well, on behalf of parents, on behalf of those of us who are involved in the private sector looking at exactly the same problems, welcome aboard.

DR. CHESNEY: Thank you very much, Dr. Goldstein. Having attended a conference by default recently on family centered care, I've become much more -- not the pediatricians, in general, are very focused on parents, but it's a paradigm shift to think about family-centered care as opposed to care that we give for families.

Well, we're very fortunate and grateful this morning to have Ms. Hurlburt here to speak to us, and we look forward to hearing your comments.

MS. HURLBURT: Thank you. Be patient with me. I've never spoke in front of a large medical group, and I can't believe I haven't asked questions already.

I'm here to represent my daughter, Ronny-Kay, who by choice came with me today to be my support because I always support her.

RONNY-KAY: Hi.

MS. HURLBURT: Generally speaking, she is an athetoid quadriplegic with extensive drooling.

We are now taking Robinul. I've had a wonderful result with one side effect being constipation to the point of the emergency room, as Dr. Pena had talked about earlier.

We went through many, many different things to get to that point, starting at school age being embarrassed, humiliated, segregated away from the other ones because of her drooling, coming home with wet artwork from excessive drooling. We call it the river.

She's very, very cognitively aware, 10 years old, in fourth grade, mainstreamed, in LD classes as well. She has a full-time paraprofessional who does a lot of observing, but yet we try to give her independence. Through independence, the head is hung down. Drooling is more excessive. Her natural positioning is this. So, it's a constant reminder all day long of head up, swallow. It's just not the natural reflex that we do have.

At one point someone in here earlier had talked about the convenience of we look at as drooling. I went through that. I went to an oral surgeon seeking help to do something about the drooling. They were going to do the surgery with removing the glands here because leaning forward all the time, those two were just consistent rivers, and then reverting the other two down the throat so she didn't get dry. She began to cry when they approached her to do the orral examination. He was wonderful. But I started to cry, and I thought am I doing this because it's really necessary or is it convenient to me not to deal with the problem.

So, she's very, very cognitive. I said, what is Mom doing here? And she said, I don't know. And I said, is it bothering you? No, it isn't. At that point I realized until it becomes a bother to her, even with the cruelty of society, I did not have the right to make that decision.

So, we furthered on in, and she got to the point to where through different things that we would use to help contain the drool so it did not get to the chest, she was called a cowgirl and many other names, and she would come home emotional. It was very hard to modify something that wasn't noticeable around her chest area.

She was sick very often, on antibiotics sometimes twice monthly, used a nebulizer regularly.

We started Robinul last May. We have not used the nebulizer one time. It has been completely excluded. It still sits in the closet. She has been on approximately three bottles of antibiotic. She still has enough saliva that the chin is still a little wet, but there's none of the drip to the chest. So, exposure to weather is not as critical and so forth.

Dr. Pena, on first meeting her, she was wonderful. She asked more questions directly to Ronny-Kay and her team of doctors did rather than myself, which I was very impressed with. She answered all of them. When asked to approach her mouth, she was ready at this time to get rid of the problem because she wanted to be accepted by society.

So, they did an oral examination and they discussed their medical language, and we tried to understand it. Then they said, we feel she's a good candidate.

At that point, she was put on the Robinul with me understanding some of the side effects and so forth, and that if I had any problems to call the office. And I did frequently, and they were extremely supportive. I was concerned about less urination. We were very active going to King's Dominion. I was afraid she wasn't going to sweat, so I called constantly. Is this going to be a problem? She was very thorough, very patient. Increase your liquids, et cetera, et cetera.

So, we really did not have any side effects. Pupils did dilate, a little bit of stomach cramping in the beginning. Fortunately, she can communicate and feed back the way she feels entirely if it's an earache, whatever. So, there was a little bit of complications with the stomach.

Once we got regulated, I think it was great. She loved it. Last year she graduated from speech therapy, which is a very big step. Normally we never expected her. And the focus in there was massaging tools. And we through an ice cream party for the graduation. It was important. It's just been very, very successful.

At this point the only thing that I find a bother -- it doesn't her. She can still focus on everything. Nothing impairs her as far as the medication, but constipation was in a very, very bad state. She had become dependent upon enemas, not me realizing that it was due to the medication. Finally, she actually said, Mom, I need to go the emergency room. I'm in great pain. I just don't see everything, even though I try to make observations.

So, on our second one, it came to me. Oh, my goodness. All the secretions in the body are being decreased here, so this is probably the issue.

The doctor did not take it upon herself to investigate the medications I had listed, which Robinul is all that she takes. There are no seizure activity or anything with Ronny-Kay. She called the pharmacist to get a feedback on the medication. Of course, there was a higher risk than many other medications for constipation.

At the second time, it was digitally removed once again. Throughout this time period, she realized the significance of stool softener and being able to swallow. So, she graduated to the swallowing of the pill. Thank goodness.

So, we had to just exclude the Robinul, get the body regulated, get it hydrated, and now we are back again using Robinul to a smaller amount in the beginning with stool softener and a little bit of fiber increase and fluid intake increase. And hopefully that will regulate it all.

Other than that one default, this medicine is like heaven to me simply because it made such a difference in her self-esteem, her ability to feel comfortable in a large group setting which she felt and knew that it did draw attention and the kinds could be very ugly. Because of her head control, that was one of the biggest things to me. Her sicknesses that were so consistent and anything she does, she has fluctuating tone. But when she tries to anything with the hand -- she is right-handed -- the head has to watch the hand. Therefore, the head, once again, is consistently staying in this down position, which is where most of her work stays and everything, which was being destroyed.

So, on a personal level for our experience, it has been a wonderful medication with some side effects, of course, and that's over a year's duration, from last May coming up to this one. She has been very happy with it.

The physical, occupation, and para at the school have all done observations as well, kept notes. Through sicknesses her drooling was more excessive, and Robinul did not decrease that. We didn't increase it during that time either. It's been very gradual to build up to where we're at now with Dr. Pena with lots of questions and observation. It just wasn't going right into it. At first I could hardly even tell that the medication was working, and I'd call and say, well, what am I supposed to expect here? It takes a little time. It must build up gradually and slowly so the body can adjust to a new intake of medication.

But if you have any questions on something I'm missing, because I am extremely nervous, please ask and I will answer the question.

DR. CHESNEY: You've done a terrific job, very descriptive. You raised all the issues that we've been talking about, but it makes much more of an effect when you talk about it.

I think what I'd like to do is hold the questions for Drs. Stiefel and Goldstein until after the break, but does anybody have questions for Ronny-Kay's mother? Dr. Nelson.

DR. NELSON: How often do you need to use the medication, and do you find the administration difficult, disruptive to daily routine?

MS. HURLBURT: I did at first simply because I had to crush the pill. If we were out and about -- and we are very active -- I would have to find somewhere to get ice cream, apple sauce, something, do a mixture. It was a very big inconvenience. Once again, graduation to swallowing of a pill has been wonderful, just water.

Right now we're doing it twice a day, one before school with breakfast, 2 milligrams, 2 milligrams after school when returning home. I don't see on our personal behalf a significant change that she starts drooling excessively before the second dose comes in. It's pretty consistent to be maintained all day by those two doses.

DR. CHESNEY: Dr. Szefler.

DR. SZEFLER: Once again, you did very well. It is not easy to talk in front of big audiences if you haven't done it a lot.

MS. HURLBURT: Yes.

DR. SZEFLER: What are your personal experiences in terms of the formulation, things like taste? When you had to use the other formulation, was it a problem in terms of pharmacies, inconvenience in terms of time, additional cost, delays, anything like that that you ran into?

MS. HURLBURT: She does have a very strong sensitivity to textures in food, medications. I had a granulator. When I did do that, it was beady. She has a gag reflex. It has gotten better. It was a big inconvenience, very much, simply because if we were out, especially if it was a windy day, I was concerned with the chest being wet. That was our initial search out for help anyway. If we did not have it with us, wasn't expecting to be out that long -- usually you're prepared when you have a child with special needs -- we would have to find somewhere to get something on the soft side to mix this to take away the taste and the texture, apple sauce, ice cream, whatever. It had to be something. Through desperation, we could get a candy bar with caramel, anything to disguise the texture and taste. And it was very inconvenient.

Now, with swallowing the pill, which has been great for self-esteem and independence, feeling that she's taking control of things, it has been much better.

DR. SZEFLER: Is taste a problem? Is it like a bitter taste or after-taste?

MS. HURLBURT: I asked her that and she's very, very capable to respond. She says it's like if I were to take an aspirin. It's bitter. It's yucky.

DR. SZEFLER: Just a couple other questions to follow up on that. Have you noticed anything as apparent in terms of dosing strategies, when to give it, when it has it's most effect, when it's best for you and her in terms of family circumstances, before meals, after meals, nighttime?

MS. HURLBURT: I do try to give it with a meal. Not that we've had any trouble with it being given on an empty stomach. It just makes me feel a little bit better that it is going in with -- never have I heard or read through research that it is affected or has more of a benefit on an empty stomach.

As far as an inconvenience to the family and so forth, it has not been because I do have two older children who are very involved with Ronny-Kay's well-being and caretaking. They're typical siblings, arguments, so forth. But we've all kind of grown into there are certain things that we are willing to give up and change and modify to benefit her as being a part of our family.

So, I don't know if I answered that entirely.

DR. CHESNEY: Dr. Edwards.

DR. EDWARDS: In terms of using the measurement tools that Dr. Pena has given you in terms of measuring secretions and also using it in school, how easy has that been to do? And also how easy has that been to get the people at school to do this as well?

MS. HURLBURT: It was actually very successful. The only disadvantage was that we had a new therapist come in who wasn't familiar with her history. The longer you're with a patient or a child, the more you learn them, and you know the drool before the medication was intervened and then to now.

As far as her paraprofessional, she was wonderful. She's with her all day. So, she could do just a drool chart on 15- and 30-minute intervals, and she would just take note. At different times, there was more drooling prominent, such as things that if Ronny-Kay was doing anything that consisted of her head needed to be up to pay attention to what was going on, not that there was lip closure, but there was just less probability for the drool. But any other times, during art activities or anything she had to work with the hand, the head was down. So, they could do a record of all of that.

There was points about mid-morning, about 2 to 2-and-a-half hours after the medication was the highest peak of maximum result I guess you would call it. It was actually last towards the afternoon, and then the drooling starting to come back not near as profuse as one point but ready for the next dose when she got home.

To answer your question, it wasn't difficult and there was no apprehension to the people that worked with her to evaluate and take note for me.

DR. CHESNEY: Dr. Walters.

DR. WALTERS: This is not at all a medical question, but I'm concerned about the cruelty of classmates. I'm just wondering if there's anything that you think could be done by the school or by the treating physicians or anyone else to educate those very intolerant classmates.

MS. HURLBURT: I think it's a big importance, and especially because she is very cognitive. It's very hard for me not to get emotional because they have been cruel. A lot of people automatically assume retardation because of the dropped head and the drooling. As soon as her head is lifted and they see here and the drool begins, some people want to turn away. They want to think that she is automatically retarded, which is very sad.

What I did on a personal level, because kids were so questioning of it, sometimes not even due to the drooling, but why do you have tissues tucked in your shirt? At a younger age, it was more of an inquiry. As they got older, it was that they couldn't stand it. It was gross.

And I think at one point Ronny-Kay herself did not know how to answer why are you drooling. She was just, Mom, tell them. She didn't know what to say.

There is a group that was called New Kids on the Block. It's puppets who have different disabilities. I had requested through our principal that she bring them in during disability awareness. They broke it down into smaller groups in the elementary school, K through 2nd and 3rd and 4th and 5th and so on, and did a skit kind of portraying who the person was. They asked me details about what I wanted to focus on, and I said drooling, why am I in this chair, et cetera, et cetera, and other diagnoses within the school as well.

Then they gave a free forum for the kids to ask any questions. And our hopes was for them to ask, why do you drool? How come you can't control it? Why do you wear this? It was successful, but still you're going to have the kids who -- just out of the attention that a child like Ronny-Kay seems to ooze out of people, from her disposition being so wonderful, it's a jealousy issue more so than not understanding or compassion, if that makes sense.

DR. CHESNEY: Great answer.

One last question. Dr. Kelsey.

DR. KELSEY: Thank you and your daughter for coming today, Ms. Hurlburt.

I wanted to follow up on what Dr. Edwards was talking about. Can you or can your daughter discern from day to day differences in how effective the medication is? Are there some days when it seems to work well and others it doesn't so much?

MS. HURLBURT: Sometimes, yes. Fortunately, like I said, we've not had as many sicknesses. The saliva is always decreased, the production, but not entirely. But there are days when she has been sick that, yes, there is more. And I know it's not producing more. I don't know if it's just that at times she's also swallowing because we're still reminding her of that. It's not like we give up the field of let's try to do this independently without medication. So, it's a constant reminder of swallowing, lip closure. We've even got the siblings in the home making habits to squeeze her face up for a kiss to constantly stimulate the facial muscles. But it does seem at times -- and I don't know medically how to answer that -- that there is more drooling than at other times.

DR. KELSEY: So, if you had something other than the pill that you give twice a day, you could give a little bit more in a situation like that. That would be a possibility.

MS. HURLBURT: Oh, most definitely if given the opportunity. As far as I would feel comfortable to evaluate?

DR. KELSEY: Yes.

MS. HURLBURT: Yes, because I do spend that much time with her and I do that much assessment with her from loving her, that whatever makes her comfortable -- and this was by her choice this time to see Dr. Pena. I would feel comfortable, yes.

DR. KELSEY: Thank you.

DR. CHESNEY: Ronny-Kay, thank you. I didn't mean to startle you.

(Laughter.)

MS. HURLBURT: She asked if she could speak here today.

DR. CHESNEY: Thank you very, very much for coming. Do you want to talk to us?

RONNY-KAY: Yes.

DR. CHESNEY: Great.

RONNY-KAY: Well, as you guys know, I am here today with my mother. Of course, this is about my drooling. I think my drooling is okay except when kids laugh at me.

MS. HURLBURT: So, that's why we're here. Right? And you're on the medication.

Say, that's it for today.

RONNY-KAY: That's it for today. Thank you.

(Applause.)

DR. CHESNEY: Thank you both again for coming. I know it was hot outside and it's awkward getting here. We really appreciate it.

MS. HURLBURT: It was a privilege.

DR. CHESNEY: Could we take a break just for 10 minutes instead of the 15 minutes and, according to that clock, be back no later than 10 to 11:00?

(Recess.)

DR. CHESNEY: Before we ask questions of Dr. Stiefel and Dr. Goldstein, we are scheduled for an open public hearing. There's nobody who has indicated that they wanted to speak. Is there anybody here who did want to speak but hadn't let us know?

(No response.)

DR. CHESNEY: Let me ask the committee then if you have any questions for Dr. Stiefel or Dr. Goldstein. Dr. Kauffman.

DR. KAUFFMAN: Maybe some of the other experts can comment on this too, but I gleaned the impression this morning from both some of the presentations, as well as the last presentation, although there is a long laundry list of potential side effects from the anticholinergic, that the one that really is most problematic is the constipation, GI problems. Is that a true perception? Because that seems to me to be somewhat manageable with osmotic and bulk laxatives and stool softeners, et cetera.

But some of the other side effects that I would have anticipated, but didn't hear about, would be intermittent difficulty with vision in school trying to focus on reading or artwork because of the effects on the eye, urinary retention, and possibly some intermittent tachycardia or temperature control in hot weather and those kinds of things. Are those really negligible or do they pop up also?

DR. STIEFEL: May I address that? Again, that was a very quick pass through that slide. Our experience is different than other folks. I think the difference in our experience is that we are just more involved in the global management of the overall health care needs of the child.

We were just also talking about that over the break that a lot of these side effects take a long time to recognize that they're even a problem. We find the temperature regulation problems particularly in the summers where the hydration issue is a major issue. Actually we've hospitalized many kids over the years that have just gotten severely dehydrated, other sorts of issues. Constipation is manageable but it is a significant management issue in these children.

We find the accommodation problems and the other things that you're talking about as sometimes a problem, but it's very individualized. There have been a couple of kids that have complained of it, but it's not been over all.

We do find problems with the central nervous system that I think are minimized. The problem is how do you assess it. I think the reason we don't talk about these things is because we don't really know how to both quantify and assess those things. These kids many times have behavior problems and sometimes very severe behavior problems.

Again, it's just sort of that one other addition to sorting this out. But as we sort out, as we remove kids -- 95 percent of our work is removing kids from the psychopharmacology that is inappropriate and sort of starting over again -- we find out and we are able to sort these things. It's not something, though, that comes out right away. Again, there is the actual cycle itself and then there's the period of time in terms of recognition of those side effects. And that changes over time also and it changes by season. It changes by a lot of other things.

So, I think they're there. I just don't think we do a good job of looking at them and recognizing them, particularly in the time that we do in terms of traditional medication studies.

We also have come full circle to realize that in the studies that we're looking at, we probably can't do randomized controlled trials, to address your issues a little bit earlier -- but I am going to expand on it -- because there is such a strong physiological effect of this medication that it never is blinded.

These are lifetime medications. I didn't make this point, but if a kid responds to this, they're going to be on this the rest of their life. There are many families, when you approach it from that perspective, that will tolerate AB/AB trials to be able to actually look so you can over time begin to sort out the side effect profile and other sorts of things. That's where we are moving towards with not only this medication, but many of the medications in kids with disabilities, AB/AB trials because, again, it's a commitment lifelong. Even the kids themselves and the adults are willing to go through that many times. But it's again how you present the package of information and how you make the argument.

DR. KAUFFMAN: And the baseline is stable enough that you can do AB/AB?

DR. STIEFEL: Ask me in two years, Ralph. You know we're a new shop.

DR. CHESNEY: Dr. Goldstein.

DR. GOLDSTEIN: We have another variable in play. Again, these children have multiple disabilities. Parents are desperate for interventions. And there is a world of interventions out there. Hyperbaric oxygen therapy, et cetera, et cetera, conductive education, all kinds of things. I'm not denigrating any of them. But parents will seek these out, particularly now on the Internet. And the variable comes into a study that it's difficult to prevent them from seeking out this other intervention in addition to. So, it makes the analysis of the data extraordinarily difficult because how does hyperbaric oxygen impact upon anticholinergic medication? Nobody really knows. We know it has an effect on GABA reduction. We're fairly certain of that.

So, I just bring up the issue again of why the size of the denominator has got to be as large as one can possibly achieve because of these other variables that are going to be introduced, and you can't tell a parent, no, your child cannot have conductive education.

DR. STIEFEL: It didn't come up and it's interesting that alternative and complementary care and the Internet didn't come up in this discussion. Again, I think families do come to us, in the long-term relationship, for guidance to what to pay attention to and to what not to pay attention to. That's increasingly become a major part of our work, helping families sort these things out.

The point again is these studies only work if you have a long-term relationship with them to be able to make those kind of studies work. Part of that is the partnership to be able to address issues such as that.

Again, some of the alternative and complementary medicines that are being put in these kids also have anticholinergic effects. It wasn't addressed but it's part of the polypharmacy issue that I addressed.

DR. CHESNEY: I have a question about two side effects that haven't been discussed. You were the only one who brought up the thickened pulmonary secretions, which I was concerned about, and the tachycardia. If we were to look at those, it would take a much more aggressive approach than the constipation and things that we can see. Are those significant enough? I also think it would be very hard for children to articulate palpitations and tachycardia. I don't know how hard it is to know that.

DR. STIEFEL: With all that's going on with anticholinergic and QTC and all the other sort of things in terms of the many indications, we haven't had it be a significant problem. The literature mainly focuses on kids with Down's syndrome and tachycardia, and there seems to be some implication that those kids are more sensitive, although I don't think the science is good enough to really say that at this point.

We haven't seen it be an issue other than with kids who are sort of on the borderline, have QTCs floating in the 440 range, somewhere down the road, and then we just push limits a little bit more. Some of the kids also that we see -- again, it comes back to the complexity issue -- have complex congenital heart disease when you're seeing kids with genetic syndromes.

So, we haven't run into it, but I think it's going to be an issue. It's just going to be like what we're involved with with Mellaril right now and some of the other drugs in regards to these kind of things. Eventually there probably would be something that over time adverse things would be reported. There probably would be problems, and retrospectively we would then come back to it and revisit that. But I haven't had it be a major problem. I haven't had to discontinue with any in our study, and I don't know if you have with your study.

DR. PENA: So far, except for the one patient who had the tracheal secretions that were causing the obstruction, I haven't had to discontinue. As a matter of fact, when I titrated it down, it improved. That's the only really adverse outcome I would say that I've had.

DR. STIEFEL: On the other hand, regarding the pulmonary stuff, it just depends on the complexity and all the factors that go in, the posterior drooling component and all the other things that go into very complex management of these kids who have neonatal histories, spent three years in the BPD units and come out vent dependent. If we are honest with ourselves about trying to sort out what these medications are really doing and how they're going into that vicious cycle, it's very, very difficult to sort out.

DR. CHESNEY: Thank you.

Other questions? Dr. Fink.

DR. FINK: Just a comment. On the pulmonary issues I think the vast majority of children with lung disease, if you effectively decrease their drooling, you also decrease the posterior drooling and aspiration. The majority of them actually do better on these drugs so that pulmonary complications are down, viral infections decrease because most respiratory viruses we now know are aspirated into the lung. So, overall the pulmonary status usually improves and it's a rare patient inspissates.

DR. STIEFEL: And if you don't dry them up completely, it comes to the titration. If you're in that balance, you don't get into problems. That's been our experience also. But it has to be the careful titration that gets you to that point.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: I'd like to just make an observation and get some reality testing, I guess, in terms of what I'm hearing.

Complexity is a major theme of all this, and variability in terms of physiologic response to the medications, variability in terms of the value of a range of efficacy and adverse event balancing that would occur both on the part of any given child and on the part of any given caregiver for that child, to parent, to foster parent, to institution, et cetera.

So, in a sense, the clinical management that involves a titration of a dose to an outcome that balances both the child's physiologic response and the outcome values, if you will, of the caregivers is how you're managing this situation.

So, then I ask myself what are we going to try and accomplish in the FDA process, drug development, study design, and that sort of thing. It strikes me you'd end up with a very complex study, and it's not clear to me, as long as you have validated measurement tools -- and frankly, you've got a pretty good list of tools compared to even the pain management area.

I guess my question is, is it really a question of how you approach the titration and outcome? It seems that good clinicians have a handle on that. Or is it really a question of formulation, having some different tools, if you will, to put into that kind of setting? What's really the major issue here? Is it just getting a better preparation and formulation?

As I think about the transdermal preparations, if you can't come up with a predictable dose response, you can't titrate a patch very easily as opposed to titrating pills or liquid preparations or other formulations. So, the formulation may be somewhat constrained by the ability to establish a set dose if that dose is going to vary patient to patient based on the complexities that you've been describing.

I guess I'm asking for some guidance about what you really see is the key issue here. Is it really the dose response study kind of issue, or is it that we just need to have some better formulations to begin to provide management tools that you need?

DR. STIEFEL: Does somebody else want to answer that question? Because that is the question.

I'll give you an opinion. A lot of it depends where you folks are at as you approach not only drug studies in children but drug studies in special needs populations in children. It comes back to that paradigm shift that we were talking about earlier. You can either do business as usual and just address those basic issues, or you can also take an education responsibility and you can push the paradigm, depending upon how far that's pushed. I don't know, and that's again none of my business.

But even if you, though, do the things that you're talking about, those things initially will be extraordinarily meaningful, the formulation questions. Again, if you look at almost all drugs that come out, this is one place where we have to be proactive in terms of titration schedule and education, folks.

Let me use an example away from this, but lamotrigine, which is an anti-epileptic drug which we titrated too fast and created Stevens-Johnson syndrome in a lot of kids. If you look at the history of things, titration, knowledge and wisdom always come out retrospectively after initial FDA in the post-marketing trials. This is one place where you're going to hurt kids and families, though, if we don't do this prospectively and at least have good guidance in regards to these things and formulations that are able to be used in a way, as you've talked about, through a broad dosage range.

However, when we talk about broad dosage range, we are not talking about an infinite dosage range. We are talking about a broad dosage range. And certainly there will have to be response to that from the private sector, but it's not undefinable. There is a dosage range that we use. Again, has that been defined? No. But it's not infinite.

I could continue to comment all day long, but to at least address those two issues.

DR. CHESNEY: Dr. Szefler.

DR. GOLDSTEIN: While they're adjusting that, let me just also say I think the model is insulin therapy for the diabetic in that one is titrating nearly on a daily basis for the severe diabetic, for child diabetes. One isn't doing blood levels as endpoints. One is looking at blood glucose levels which are some indicator of something, but many of us aren't quite sure what. So, we're dealing in this type of paradigm where the endpoint here is the amount of drooling, but what we do have is this horrible upper motor neuron lesion which is affecting tongue mobility, tongue motility, pharyngeal motility, and in each child and in each subject, that is somewhat different. So, again, it's this issue of in that particular child with that particular combination of neurological lesions, the only measurement tool that you've got effective at the moment is the degree of drooling and how are they handling their sputum.

DR. NELSON: I agree with what you've said, but let me just make one observation. The difference I think in this context from diabetes is we can all agree that you should have a blood sugar of X. What you want to do to get there, how many times you want to take your insulin, and all that kind of thing may vary as far as lifestyle issues. Correct me if I'm wrong. You have an overlap of efficacy and adverse events precisely in the dosage range that you're going to be working with potentially to where the outcome itself that each individual child and parent would accept is going to vary in a way that's very different than the insulin example.

DR. GOLDSTEIN: That's correct.

DR. NELSON: So, you're not only changing the dose you might need. Everybody responds differently to insulin. But you're changing the actual outcome measurement at the same time, which is what makes it particularly complex.

DR. GOLDSTEIN: Yes, because we don't have an objective endpoint, i.e., blood glucose levels, that we can be comfortable with in terms of saying this is a range of blood glucose levels which we will accept. Here what we're saying is here is the range of salivation which is a very imprecise measurement at the extreme. So, we are balancing the adverse effect of cutting down on salivation against what is acceptable social impact of drooling.

My daughter is a juvenile diabetic and checks her blood glucose levels six times a day. She's an adult now. She's accepted this. She knows how to handle it reasonably well. But her protocol of therapy is very different from somebody else's who is also a juvenile diabetic. The best we could do was educate her to the range and to certain endpoints that she's got to be sensitive to as a young adult. That's the only reason for my analogy. It's not a dose effect because a certain amount of insulin at 2:00 in the afternoon will have a very different effect than before she goes to bed.

DR. CHESNEY: Dr. Szefler.

DR. SZEFLER: I just wanted to follow up on two points, one that Dr. Chesney made and another one Dr. Nelson made in terms of this formulation. I think what we're trying to grasp from you is I think we've got a situation where there's a drug that's helpful, but it's problematic in terms of what we think is a narrow range between beneficial and adverse effects. It would seem to me, in hearing the discussions, that you have a product that was developed for something, used for something, I think for acute secretions, although I don't think it's indicated for that, but now you're using it for continuous secretions. It would seem logical to me, to follow up on Dr. Chesney's point, that maybe a recommendation in the formulation development like a sustained release product might help.

But what I don't have a good feel for is the percentage of patients who are likely to respond and if the effect on secretions is one of the first indicators. I sense what happens is that if somebody doesn't get a response, then they escalate the dose, and when they escalate the dose, they kind of get a high peak. And then you're going to run into crossing that threshold where a higher proportion of patients may get the adverse effects.

Do you think making a recommendation to investigate the formulation of a sustained release preparation would add something to your pharmacopeia that would make it more convenient, reduce the problems with taste, and maybe make an effective preparation for this target population rather than taking the next extemporaneous preparation and using it in areas that may create jeopardy because of misuse?

DR. GOLDSTEIN: The answer to both questions is yes. We're going to find in this heterogeneous population a population of children for whom a sustained release medication will serve its needs quite adequately and not at the moment worrying about the titration issue. We're going to find another population which is so unstable, in terms of its activities of daily living, that sustained release might be extremely dangerous.

So, again, if I might use my insulin example, I think we haven't defined that population and we will need to define it, which is why these studies will have many beneficial side effects in terms of information and data about the characteristics of this population.

DR. CHESNEY: Dr. Stiefel, you were going to respond.

DR. STIEFEL: Again, it's a heterogeneous group. There are going to need to be multiple formulations, not only sustained release, probably a transdermal system also, perhaps even looking at new and novel delivery mechanisms in terms of looking at the pharmacokinetics and absorption through, again, many of the other things that are looked at. I don't think there's going to be one answer for everybody. Obviously, you just heard that from the most important source, that for this young woman, learning how to swallow a pill was a great thing, but that doesn't work for everybody. So, we're going to need a range of things. I think using examples such as clonidine or stimulants or any of the other things that we use that need a broad titration range, you're going to need multiple different types of products to address this over time, and one thing will not fit for all.

DR. CHESNEY: Dr. Fink.

DR. FINK: It strikes me that this is primarily a formulation problem but not exclusively one. Obviously, long-term time-released products are one approach. The other one that sitting here just fascinates me is what about the use of a reditab where you dissolve it on the tongue and you might even get more activity at the site where you want activity very quickly and you don't even have a swallowing problem. So, looking at something like a reditab formulation where it dissolves and you don't have to swallow a pill might enhance both efficacy and convenience of treatment.

DR. STIEFEL: We would encourage novel delivery and formulation.

DR. CHESNEY: That's great. Why is it called reditab? Is it at the ready?

DR. FINK: Well, Claritin is out in that now where it literally dissolves on the tongue in 2 to 3 seconds and you can swallow the liquid, but very rapidly dissolved on the tongue and it's sort of a soft tablet that doesn't require swallowing.

DR. CHESNEY: That's great.

DR. SPIELBERG: A question for FDA because formulations don't grow on trees. You need sponsors to do this.

There are two questions. One is current exclusivity and patent status of the compounds we're talking about. And two, do we really want to develop any of these old dogs, or do we want a better drug?

Those are the two critical things because if we're going to go forward and really solve the issue and come up with something that actually is going to be both user friendly for the kids and for the parents and pharmacologically appropriate, we have to deal with are we happy with the current spectrum of activities and targets associated with the current compounds available. What is the status of all of those compounds? Who owns them and who is going to do it if we are going to go after old compounds? Or are we really talking about discovery here?

DR. KELSEY: Well, you're absolutely right that we're at the mercy of the sponsors. FDA reviews what is brought to us. We're very early in the process with this particular indication and that, combined with the fact that we have limited knowledge about this patient population and studying any kinds of drugs in this group, FDA as well as the division, we've come to you all to publicize it and to get your guidance.

The antimuscarinics that Dr. Mathis talked about are, of course, have been around for a long time. I can't tell you about what specific patent life any of them may have left, and the issues about use patents and all that sort of thing get very complex. I'm certainly not an expert on it.

DR. SPIELBERG: That is a fairly key point, though, in terms of whether FDAMA is or is not a mechanism for these compounds because whether there are incentives around still or whether we need another mechanism for driving it for this particular class of drugs really is critical in terms of our understanding.

DR. KELSEY: Yes, sure. That, of course, goes way beyond our level at the review division as far as what FDA's policy is going to be. That's really a legislative issue, what sorts of additional incentives Congress might give for this sort of thing. We review what comes in, but I think that this type of a forum can stimulate sponsors to at least think about different things. We don't have patch formulations. We don't have sustained release or reditabs and that sort of thing. I'm sure that people could get additional patent life there.

Of course, there is nothing approved for the indication of drooling. I think I might have misspoken earlier when Dr. Fink asked a question. This is not approved for drooling in adults or children, of course. So, I think that there are some opportunities there for industry to develop these compounds.

DR. SPIELBERG: The latter point is critical, though. If they're not approved for drooling, you need a clinical efficacy program. There's no way around that. It's not just a formulation issue. It's a new indication. So, whether it be a better chemical entity or whether it be a redefining of one of the older drugs, it's a real development program.

DR. CHESNEY: Dr. Nelson, did you still have a question?

DR. NELSON: No. I was just pointing to Steve.

DR. CHESNEY: Dr. Walters.

DR. WALTERS: I'm trying to think about a design that would work with the drugs that are currently available, and the only analogy I can think of at the moment is from a very different field. There was a cardiac arrhythmia suppression trial that involved multiple drugs and a titration phase that was tailored to each particular patient. So, the simplest design that I can think of would be a head-to-head comparison of two or three of the best existing drugs with the titration phase at the beginning and then a large enough sample size that one could have some confidence in the result.

So, Judith, you're an expert on this kind of issue.

DR. O'FALLON: I think this is an ideal situation for doing your AB/AB or ABC/ABC/ABC type study. Probably AB/AB is better.

But he was talking about doing a crossover study. There was one in our packet, a 1989 study, that really I thought was extremely well designed, had a terrible time with the analysis folks. They couldn't figure out what they found. But the design would be a model. They had a baseline. Then they had a treatment period. In this case it was a 2-week. I don't know. You would have to talk the issues. But there was a week of titration and then a week of, I call it, cruising altitude. Then they went to a washout period, and then the second drug, or in this case placebo, and again a week of titration, a week of cruising altitude. Then they compared the results in the second weeks between the two.

I think in this kind of a disease where the drooling goes right back to as bad as it was as soon as you remove the therapy, this is a perfect example of a situation in which that would work.

Now, that doesn't answer the question of long term. It will address does it affect the drooling. Is it efficacious in drying off the mouth and short-term toxicities.

If you're going to do long term -- and I think you have to from everything I'm hearing -- then you probably have to roll over into a continuation study, which is another very well adapted thing where they would choose one, maybe even still be blinded. Who knows?

These would, I think, need to be blinded because the one piece of information that I could get out of that '89 study, as far as I could see, was that there was a placebo effect. My own experience with blinded treatments in things like pain, hot flashes, and so on, having done a number of these studies, there is a placebo effect. At the beginning, everybody is optimistic and it just happens. So, you have to be able to sort out the placebo effect from the true efficacy. So, I think they do have to be blinded, if at all possible, but then they can go on into the long-term and just be doing a good job of getting the toxicities in the long-term.

DR. STIEFEL: I agree with everything you said, but let me also talk about placebo effect in kids with special needs. I want to introduce a concept of placebo effect that's additive. I can tell a teacher or education system that I'm going to put a child on medication -- it doesn't matter what it is -- and buy that child another year of placement just because of the hope and faith that that medication will make a difference in terms of the problems that the child is having, whether that's drooling or whatever that is. You then add to that in the kids that have the cognitive abilities to be able to look into that, that child is also hopeful, plus the caregivers that are hopeful. And I'd say 1 plus 1 plus 1 probably equals about 5 there. So, we have efficacy that approaches 40 or 50 percent in many of these medications and placebo that approaches almost the same amount. So, it's very, very interesting and very difficult.

Again, we're not representing that these are simple issues. Our job is to give you information to be able to address these very, very complex issues and to see if, in this crisis that we are involved in, whether or not there is an opportunity to perhaps do some of the things that we're talking about.

DR. NELSON: I guess I'd like to pursue that a little more because what I had heard earlier was, when I had asked the question about blinding, which was really meant about an assessment tool issue, that the notion of being on a medication that could potentially not be efficacious wouldn't be acceptable to parents, undercutting the possibility of that kind of trial.

We had started off by saying we're going to assume efficacy, which was sort of a physiologic assumption, but now, since we have to do it for a new indication, suddenly we're back into designing an efficacy trial. And now we're back into placebos even though we started off the morning by saying let's assume it's efficacious.

I recognize the regulatory impediments, but do we really think we need a classic efficacy trial? What would be the purposes of a placebo arm? I guess I'm just getting a little confused about the direction on that particular point.

Would it even be acceptable? I could see an active control equivalence trial even if it's defined as a superiority to try and eliminate Bob Temple's objections to those kinds of trials. So, I guess I'm a little confused. I just want to focus on that issue a little bit.

DR. CHESNEY: Could I just intervene for a moment? We're theoretically just asking directed questions and now we're getting into what they really want to hear from us. So, could we ask Dr. Kelsey to give us our mission? I think you're on the schedule for that.

DR. KELSEY: Yes. I'm going to go back over the questions. Well, I feel like we've gone over these questions several times already this morning. So, I'm not sure how much new ground there's going to be, but maybe this can pull it all together.

This has been very useful for us at FDA. As I said, we're new to the issues surrounding study in this patient population and these comments that we've heard this morning have been very beneficial.

I'll go back to the questions that we presented initially, and I guess, if it's okay, Dr. Chesney, we'll just go question by question and discuss it that way.

So, the first one concerns adverse events and how they can best be assessed in this population. Some of the issues that I noted down here have to do with frequency of professional assessment. Certainly the parents are important in assessing the day-to-day impact of the medication on their child. However, it's also clear that sometimes the parents miss things and how often are the professionals going to be involved. What sort of training do the parents get to assess adverse events? Specifically, in clinical trials, would you advocate use of checklists, training sessions for parents, that sort of thing?

Would small dose-ranging safety studies be appropriate in the beginning to look at small groups? We talked about the fact earlier that it might be difficult to take a subset of the overall population of people with cerebral palsy, but it might be reasonable to have some small initial studies.

So, those are a couple of things that I noted after this question in my notes.

DR. CHESNEY: Could I ask you to go through all the questions? We may not start at the beginning. I'm thinking we might go right away to number 2. But if you could cover all of them and the issues that you want to be sure we address.

DR. KELSEY: Question 2 is the formulation question that we discussed in the last few minutes. The suggestions for the patch or reditab or sustained release or other formulations are certainly interesting.

The concentration of a liquid formulation. What would be appropriate in terms of being able to titrate in very small doses? The possibility of using a couple of different dosage forms, going back to the diabetic analogy, to having a sustained release or patch type formulation to act like NPH and then supplement it with a liquid formulation as needed, analogous to regular insulin.

Dosing frequency. We're going to want to have some PK studies. Even though we agree that these compounds are going to work in the same way that they are in adults, the PK will be different or it will likely be different. So, we would certainly want to look at the PK, and from that come up with optimal dosing schedules.

DR. CHESNEY: Sorry for interrupting, but are you actually talking about blood levels for PK?

DR. KELSEY: Yes. Certainly determine the half-life in kids and use that as a place to start your dosing schedule.

Question 3. Since therapies need to be titrated, guidance on dosing is necessary in product labeling. Please discuss the labeling tools to help caregivers assess the benefits and side effects of these medications.

We talked about this quite a bit in our preparation for this committee. We started off talking about who were the most appropriate people to assess both efficacy and adverse events in this patient population. Certainly I think we all agree that the caregivers are the people who are most familiar. But there's a range of antimuscarinic effects, and certainly it's complicated, as Dr. Stiefel was saying, by the status of these patients and polypharmacy and the rest of it.

What can FDA do? Looking down the road when we have sponsors come to us and want to develop a product for this indication, what can we do to direct them to come up with something in labeling -- the broader sense, not just the patient package insert? What can we do to help the caregivers do the best job possible in dosing these patients so that they get the benefits with the minimum of side effects?

The fourth question. This is the ethics question. Are there additional processes or procedures that need to be in place to ensure the safe and ethical conduct of studies in this special needs population? I thought that the ethical advice was probably the clearest that we got. Certainly looking back to Dr. Wilfond's presentation, we're on the top row of his chart, and it would be reasonable, based on the potential benefit, to study these drugs in this patient population.

It would be desirable to have patient assent in at least some patients, but it's recognized that it's not possible to do that in many of them. I guess what I heard was that this should be balanced. We shouldn't focus on institutionalized patients alone, but that it would be reasonable to do these studies in a range of these patients.

DR. CHESNEY: Thank you.

I'm tempted to begin with number 2 because we've already, as you indicated, done a fair bit of discussing of that. That seems very kind of hard core science. So, questions or further comments addressing characteristics important in developing a pediatric formulation. I think we're being asked also about how to individualize a dosing regimen and the issue of having to obtain blood samples to do PK determinations.

Comments? Dr. Nelson.

DR. NELSON: I'm trying to think through in my own mind if there are other examples where you want a formulation that allows you to titrate to the extent to which it seems you want to titrate, but yet have a sustained effect, without getting into a situation where you have to create 14 different types of patches. With pain and theophylline, there you have sustained release, which is possible, and you're measuring blood levels. For pain I tend to use morphine and other kinds of things.

I don't know. There are examples but it just seems to be a little bit more complex. The ability to titrate on a short-term effect seems to be working against the desire to have a preparation that you only need to use once or twice a day.

DR. SPIELBERG: Skip, I think the reason is that we're using drugs for which the desired outcome is simply a side effect, and the drugs were developed for totally different purposes. Therefore, we don't have a therapeutic index to deal with here. If we had increased specificity for the target of interest, then you're talking about a drug designed for the specific indication. Here we're talking about drugs designed for totally different purposes, the side effect of which is dry mouth. So, now we're saying we want dry mouth for drugs that are designed for other purposes, and I think that's why there's so much of the struggle in terms of titratability.

There are novel delivery systems that can begin to get into these kinds of things without going into any of the technical details. This is why I asked the question. If we wanted to solve the problem, forgetting what's out there now, do we want new drugs or do we want to try to struggle with the old drugs? If we are struggling with the old drugs, indeed, what you're doing is looking for one of a myriad of effects of the drugs and trying to get to a tolerable point where you get that side effect, if you will, predominating over the other effects of the compound. It's going to be very hard to do, and therefore you're going to need a great deal of individualization with respect to dosing.

DR. CHESNEY: That's probably an important question to answer because the agency has been asked about this drug or about this group of drugs. So, from their point of view, they need to look at this drug and the current formulations.

DR. SPIELBERG: In which case, it's going to be very, very hard and require a great deal of individualization of therapy. As Skip put it, it's basically a series of tolerable or intolerable side effects in an individual patient, each of which needs to be in the context of all the other medicines that the child is taking since a huge number of the compounds that they are likely to be taking will also have autonomic effects.

DR. CHESNEY: One problem, though, is that this is not a large market, and how do you invite a manufacturer to develop a new product? And won't that take just as long as it might to work out all the details with this product?

Dr. Wilfond has something burning to tell us.

DR. WILFOND: I was just thinking of your comments. It certainly strikes me that it's not at all uncommon to have to make very challenge individual decisions about drug level. Theophylline is a perfect example of that.

But with regards to your comment about exploiting a side effect and that being problematic, that's a fairly standard thing. I'm thinking Viagra, minoxidil. There are lots of examples where drugs developed for one purpose are used for one of their side effects. I don't think it's inherently a problematic thing.

DR. SPIELBERG: But it's entirely dependent on therapeutic index, and it's dependent on the dose and the serum concentrations associated with the desirable and undesirable side effects and the ability to separate those out for an individual compound. That's the quandary.

DR. CHESNEY: Dr. Mathis.

DR. MATHIS: Just in response to your question, Dr. Spielberg, obviously we would welcome any new approach to treating this problem. But it's important to remember that the antimuscarinics have been used successfully for this indication off label, and so I think that we'd also like to encourage sponsors to develop those products which are currently being used, as well as welcoming novel approaches. But there aren't any pediatric formulations of the antimuscarinics, and any development in that area would be very helpful.

DR. CHESNEY: Dr. Fink and then Dr. Gorman.

DR. FINK: As I listen to the discussion as it occurs, it also seems clear that the other thing we need to do is encourage the academic community that we really need to know more about this clinical problem because although we're focusing on drooling and the salivary gland, I would at least maintain that this is really more an issue of upper airway function in the neurologically impaired individual. If you look at some of the simple things that could explain day-to-day variation in drooling, nasal congestion. If your nose is stuffy, it hurts to swallow, and I'm absolutely sure in neurologically impaired individuals, upper airway obstruction, particularly of the nose, has a big impact on their drooling. So viral infections, allergies, untreated allergic rhinitis, untreated perennial rhinitis is going to have a bit impact on the amount of drooling. So, one of the things we need to say is we need to have a better understanding of this, better ways of assessing which components are leading to it.

We haven't even touched on the sleep disorders that are related to this, which is a whole other bag of worms, but maybe dwarfs nasal congestion and so on tremendously. Maybe we shouldn't even be looking at drooling. We should be looking at the sleep effects of this whole constellation of symptoms because if you improve sleep and patients are more alert during the day, maybe they'll swallow better.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: First a comment to the experts and individuals who advocate for the children and patients with the condition of drooling. I heard several times this morning for a change in the paradigm or people to push the envelope. I'm now sitting on an FDA panel where I have the agency asking me to consider developing clinical trials for an off-label use in a group of people this drug has not been approved for. So, I think this is a very proactive, different group of people. The paradigm has, in fact, changed and I think that needs to be recognized. If I have now stepped over some legal boundary and a thunderbolt is about to hit me, I'm sorry. But this is very different from the usual behavior that we think of in our regulatory bodies. This is not what they usually do.

Secondly, the word "titration" has been used interchangeably between the desired outcome, which is the control of drooling, and the fact that this has a very steep dose-response curve and a very narrow therapeutic index, all of which make the drugs that we're looking at incredibly difficult to titrate for the desired effect without the adverse event. I think if we had a drug with a higher therapeutic index and you could control drooling without constipation or tachycardia, that we wouldn't be having this discussion because parents or caregivers, whoever they would be, would reach their efficacious outcome and then not have to deal with the side effects. Then it would just be a matter of putting out a formulation that allows parents to titrate.

So, I think that Dr. Spielberg's concern about either whipping old dogs and trying to make them do new tricks or creating a new dog becomes a very important issue and goes back to whether if this is FDAMA-able. If glycopyrrolate has FDAMA stuff, we can whip the dog a little bit, but then you're going to have to find inside our regulatory body the ability under -- this will reveal my ignorance. What was this drug approved for?

DR. KELSEY: It was originally approved back in 1960 for GRD, and it's also used by anesthesiologists intraoperatively to decrease secretions.

DR. GORMAN: As an approved use.

DR. KELSEY: Those are approved uses, but they were only studied in adults.

DR. GORMAN: I guess there could be some pressure put on the sponsoring company to create a pediatric formulation for the drug. Some.

Thank you.

DR. CHESNEY: I'm thinking that maybe we have discussed number 2. I think the committee is totally in agreement with a new formulation for children, and we've got some original ideas of new ones that might be developed, but certainly to make a preparation that's palatable, that tastes good, that feels good, and the dose is appropriate to titrate small amounts.

So, I think unless you want more information on that question, I'm thinking that the core issue is how to evaluate for adverse events and then number 3, which is very closely related, which is what tools to use. Is that all right with you if we go ahead?

DR. KELSEY: Yes, absolutely.

DR. CHESNEY: So, what are people's thoughts about how to assess the adverse events in this population? I guess that goes to everything from whether they need to have cardiac monitors on and, if so, for how long and how to evaluate saliva production and written tools and who is going to do the assessment? So, who would like to start? Dr. Fink.

DR. FINK: I'm not sure I'm going to help the discussion any with this comment, but I think that potentially the most important adverse event often in this group is pain or discomfort. Unfortunately, that particular side effect is really only assessable either by the individual, if they're able to communicate, or by the caretaker. I'm a little worried that the tendency is to say use outside observers. In many of these children at least, outside observers tend to markedly underestimate problems and symptoms, and you really have to go with the caregiver. So, I guess my vote there would be we've really got to have the caregivers heavily involved because transient observers usually don't understand the problem.

DR. CHESNEY: Yes.

DR. FUCHS: I guess actually I want to tie questions 1 and 3 together because we're talking about such a heterogeneous population. We've mentioned subgroups, and it may be that this is a staged study because you've got children who are in home and school so that maybe you can have the patient, the parent, and school teachers do all of this assessment, and obviously the physician. Then you've got those who are only at home, so you'd leave the teachers out of this, and maybe you'll have a speech pathologist or a home care nurse who comes in and can do this. Then you've got the residential care patients who really, depending upon where they are, may not even have a parent to watch them. That is mainly a nurse or a nurse's aide. So, you've got all of these steps and these subgroups that I think you are going to have to almost study them a little bit individually and figure out all these adverse events because what may be an adverse event in one group may not occur in the other. The ones in residential care may have tons of adverse events, but no one is really able to assess them appropriately because they don't have the communication skills, they don't have a parent. So, I think we're looking at a lot of different groups and you're going to have to do this very separately.

DR. CHESNEY: I think that's a good point.

Now that we have PPRUs, let me ask Dr. Kauffman, could heart rate, sweating, pupillary dilatation, that kind of thing be done in a PPRU? And how would you envision practically doing something like this?

DR. KAUFFMAN: I think those are primarily objective physiologic measurements or observations that can be done. I think those could be done in multiple environments. I don't think that most of those observations would have to be done necessarily in a professional care setting. We do GI Ph probe monitoring at home. We do other kinds of monitoring in the informed or supervised home setting. So, I think some of this could be done. Particularly if you're involved in a long-term study that's been advocated here, I think we're going to have to look for ways to do this in the child's life setting, and I think that's doable for most of them.

Something that's going to be essential here is for us to have a consistent, formal way that the caretakers are trained to look for the most important side effects. The point has been made this morning that people don't tumble to the fact that something is going on as early as they might have. That includes, as a part of a study protocol, training the key persons to be on the proactive lookout for these things, so they're trained to look for constipation if that's the most common side effect. They're trained to look at the pupils of the eye at periodic times, maybe a certain time after each dose. I think we could even train them to do a very simple visual accommodation test that would be easily done by the caretaker. Certainly blood pressures, pulse rates, other physiologic responses that we might want to monitor.

I'd have to think through it, but I'm not sure we would want to buy into doing extensive electrophysiologic monitoring in these kids in their daily life. I think it would be very disruptive and invasive and probably destructive in some ways.

And then the kids that are able to self-report, I think we could use self-report scales. There are non-self-report scales, as has been pointed out earlier, that are used in neonatology and intensive care units and those kind of settings that do attempt to assess comfort and discomfort and pain. Those could probably be adapted for this kind of work.

So, yes, I think this can be done. I don't think it has to be done in a formal study setting like a PPRU, but I think that most of the PPRU sites, as well as other centers around the country, have the people that are expert in doing this kind of thing.

DR. CHESNEY: The PK studies --

DR. KAUFFMAN: Yes. I think the study design that has the most appeal to me, listening to this conversation this morning, would be the for the primary efficacy. The drooling is a rapid response. You titrate that. You can see the response to that fairly fast. If the primary outcome variable was quantitating the drooling, that could be done in a fairly short run in, short efficacy period that could be blinded and comparative in parallel randomized groups, and then, as was pointed out, roll into an open-label longer-term study for tolerability and safety.

The PK work could be done in that short-term blinded period. And it's easy. I say it's easy. At least at our site, it's easy to schedule a kid -- and it is in other sites too -- to bring the child in scheduled for 24 hours or whatever to do it. It's technically easy. It may not be easy emotionally, and there are the ethical considerations. But we do this routinely in children in a very child friendly, compassionate, noninvasive way so that we can sample small blood samples over a 24-hour period with one stick and the child is not inconvenienced or uncomfortable while that's going on. So, I think those kind of things are surmountable. They're challenges, but I think they're surmountable.

While I have the platform, one thing I wanted to point out is I think we have to be thinking in terms of the pharmacokinetics. It's been pointed out that there's a wide range of response in these kids. That could be due to a number of factors, one of which is with these kind of compounds that tend to be quite polar is the absorption characteristics. I suspect that the absorption is all over the place, even in the individual child dose to dose. With this kind of molecule, typically the absorption is very erratic. It's incomplete from the GI tract, and it's very dependent on what else is in the gut and the formulation that it's administered with. These are being given in all sorts of things, ice cream and apple sauce and who knows what else.

(Laughter.)

DR. KAUFFMAN: So, I think one of the things we would want to consider is designing the PK piece of it so that we could get a very good handle on what the absorption characteristics are with the various delivery systems that we decide to evolve. That may be much more important than the elimination kinetics by disposition of the compound in terms of explaining individual patient response. There may be individual pharmacodynamic responses too that are much more difficult to get at. For oral administration of these kind of compounds, if I was going to put my money on the thing that we're going to find most important in terms of variation in response, I would be looking at absorption characteristics and kinetics as the first thing to look at.

DR. SPIELBERG: Just to add on one more thing, because of the GI side effects, if you change small bowel motility time and gastric emptying, your absorption characteristics are going to change. So, to the extent that one child or another has more or less in the way of GI effects -- and many of these children already have GRD and GI upset from their primary disease -- that can be a major issue.

DR. KAUFFMAN: This is a major argument for transmucosal or transcutaneous delivery systems which could be very advantageous.

DR. CHESNEY: The other issue is the polypharmacy. Presumably the other four or six or eight drugs that they're on, leaving out the complementary medicine, are going to affect GI motility and affect absorption and so on, and every child is going to be different in that regard.

A quick question, also very naive. If absorption is a factor, how many children would you have to look at? How many times would one need to look at the same child on different occasions? Obviously a very naive question.

DR. KAUFFMAN: I don't think I can answer that because I don't know what the range of variability or the variance is. We'd have to do some pilot work I think to see. It's been pointed out it's a very heterogeneous group and the characteristics of their gut behavior, as well as other characteristics of the kids, is going to be so variable that I think it's going to take more than we typically would enroll in a typical PK study with otherwise healthy children. So, I think we're going to see enormous variability, with subgroup characteristics, and we're probably going to have to be willing to look at a larger group of kids than we would in many similar cases.

Dr. Nelson's got a comment.

DR. CHESNEY: I'm going to turn to the right-hand side in a moment. Go ahead.

DR. NELSON: Ralph, if you're correct in the hypothesis that absorption is a major factor in the variability, you presumably then would find a dose response that might be a little bit more predictable except for all of the variables that have been mentioned that impact then on the response of the child to the medication which would involve all of the other medications, for example, that would also have these same kinds of physiologic effects. So, you'd have to, in working that out, end up with a fairly complex study.

As I think about the labeling issues, I go back to the slides that I think Dr. Mathis had about effects of atropine in relationship to dose and the like. I think of other medications that we use through a range of effects. One possible outcome could be an understanding of the sequence in which these side effects take place, so that I would know that if I gave X dose, I get a certain response. As I increase the dose, I begin to see other responses. I'm thinking of dopamine. We all dial it up and down to get different responses.

The question would be, even if it's a variable dose at which you see the balance between the good side effect, no drooling, and the bad side effect, constipation, could you find an invariable sequence, for example, so that I as a clinician would know that as I titrate up the dose, certain side effects appear or disappear, depending upon that level?

What strikes me as very different about this compound compared to early development compounds is we know the safety profile pretty much. We can target measurements to the side effects we want to study, which is often very different where we target an efficacy outcome and then we say, oh, by the way, let's just see what happens in terms of the safety and then we get all the adverse event reports. Here you could actually target specific adverse events for measurement, which is a very different setting.

DR. KAUFFMAN: Muscarinic pharmacology is the oldest, most classical pharmacology. It's the first chapter in Goodman and Gilman, and it's classic receptor agonist/antagonist pharmacology with receptor subgroup types.

So, theoretically you could do what you're saying. I don't know if it would work clinically, but the curve that was shown this morning with atropine is a classic sigmoid dose-response curve. Theoretically we would be able to do effective dose 50's for the major predictable dose-related side effects and the desired effect and see where in the concentration range those are differentiated. Then it would at least give us a guide as to what concentration effect we can anticipate. I don't know in the clinical setting if that's achievable or not, but it should be our goal if we can move in that direction.

DR. CHESNEY: I think that would be one of the major contributions.

I was concerned. Dr. Mathis, I think, mentioned this morning that you can have some individuals who have no effect on salivation but have toxic effects and other responses. So, it may be highly variable, but that's the kind of information you could get for us.

DR. SPIELBERG: Remember, this particular drug was developed as a GI drug.

A little bit of history. Otto Loewi won the Nobel Prize, I think it was 1921, for cholinergic transmission. The apocryphal story was he got the idea in the middle of the night, wrote it down on a piece of toilet paper and flushed it, and it took two years for the thought to come back.

(Laughter.)

DR. CHESNEY: That is scary.

DR. SPIELBERG: I don't know if that's true. DR. KAUFFMAN: That's an argument for constipation, isn't it?

(Laughter.)

DR. CHESNEY: One last comment, Dr. Stiefel, and then we'll break for lunch.

DR. STIEFEL: I just want to punctuate the comments that just happened. Robert Ward, head of our group, has looked at this. We've had the same discussion in preparation for this. We agree that the absorption, once removed in terms of that variable, with these quaternary amines which are the primary subjects that we're looking at, which are very polar, as you've talked about -- and again, those that have much less tendency to cross the blood-brain barrier are first looking at -- I'm intrigued by Dr. Spielberg's thoughts about new directions to go, but that's probably beyond the scope of what we're talking about.

We believe that if the absorption, first of all, was ever studied in these kids -- if you look at all the other things that have been done in terms of all the other medications, nobody has ever even looked at the questions that were raised. You would be horrified just from an empiric standpoint as to what you would see that we would be able to actually translate to many other medications that have absorption problems, first of all.

And then, secondly, if that variable was removed -- and again, that's where my challenge to a novel delivery, either transmucosal or transdermal. If you remove that, we think that actually you would be able to develop dose-response curves.

Then the only other piece is I actually do think one needs to find a balance. I think there's been somewhat of a misperception, at least from my perspective, that we want to titrate these things every minute. I think the insulin analogy is an appropriate one, but our experience has been the opposite of that. We want to find that balance over time where the drug levels remain the most consistent, particularly those with central nervous system effects, within the nervous system over time. We want to find that balance. We don't want to go up and down every day. Most families, even though they have the capacity, over time end up not doing that because they get into a vicious cycle of side effects and other sorts of things, particularly the CNS side effects. So, we actually move towards a balance and, again, think that the comments would be very, very appropriate. Just a differing viewpoint.

DR. CHESNEY: Thank you.

Jayne Peterson has just pointed out to me that we've completed question 2 and we're well into 1 and 3, which only leaves 4. So, if there is anybody who would not like to continue the discussion, since we do have food over here, please put up your hand. Otherwise, we'll just keep right on going.

(No response.)

DR. CHESNEY: All right. We'll keep right on going.

Other comments, questions? Dr. Walters.

DR. WALTERS: Are we going to 4 now or not?

DR. CHESNEY: I think still 1 and 3, unless Dr. Kelsey tells us he has enough information.

DR. KELSEY: No. I think we should finish up 1 and 3 unless there is no more to be said. I said earlier I think 4 is going to be pretty quick.

DR. CHESNEY: Coming to number 3, which are the labeling tools, and also to see if the committee is agreed that the caregiver should be the primary person recording the long-term information, whereas the PK data obviously and that testing would be done probably in a PPRU.

Any disagreement about caregivers? Dr. Szefler.

DR. SZEFLER: I think the importance of the caregiver is to establish the baseline because it sounds like the baseline can be variable. So, having a sufficient period of time and a careful observer would be very important to establish that baseline and get some handle on the degree of variability so that you could detect an effect. That's where it gets into important questions like defining your response variables.

I have a suspicion that in these patient populations and where your group could be helpful is to draw upon your experience to say who are responders and who are nonresponders because I have a feeling where you get into trouble is when you push the dose in the nonresponders and you don't have either the classification variables in terms of the patient or the level of knowing when to stop. That's probably where the problems come in, besides the rapid absorption that can occur with things like the liquid.

So, I think in terms of the observer, the caretaker, whoever it is, whether it's the parent or the foster parent, I think the care in institution is probably too inconsistent and you would just have daytime measures, which would miss potentially nighttime measures. So, I don't know how that gets done unless there's specialty care centers that do research, and there may be certain centers. I don't know all the ethics of that in terms of how that's checked, having outside reviews do it, but I think some consistency of the observer, both in terms of the baseline to get a good baseline and then the follow-up, becomes very important.

DR. CHESNEY: Dr. Stiefel.

DR. STIEFEL: I don't think this is as hard as we're making it. The first phase studies, which we've talked about, are critical and very doable, and I think they're there. They're very important not only in terms of this but in terms of paving the way as to where we move with many of these medications.

The most difficult thing that we run into is actually defining the outcome that we're going to actually be looking at in terms of efficacy. I think what you've heard presented this morning is a broad range of outcomes. For one child it will be the social victimization that occurs because of the drooling, and you'll titrate that very differently than a child who has main problems with aspiration, titrate that very differently than another child.

We approach caregivers just as I approach training a resident. I believe that they're extraordinarily sophisticated. Many times the parents are remarkable, and we spend a lot of time training the caregivers.

I think we have plenty of outcome tools actually from a broad range of things to be able to assess these things, and you've heard a broad range of presentations. If you put that together in terms of a cumulative whole, we have the tools to be able to assess the longer-term second phase studies.

So, the real issue is actually defining what is the outcome that you're going for in terms of efficacy when you move and define efficacy beyond just is there an antimuscarinic response. Once that's defined, I actually think it becomes very easy, and we find that the difficulty is determining what outcome we're going for and then tracking that.

So, once that's done, my only plea is, even though we talk about the importance of the caregiver, I think the importance of a consortium and people who are actually trained in these areas to be able to help the family and the child determine what those outcomes are and then have the sophistication to be able to partner not in an objective means separate from, but to be able to partner in a relationship and team to be able to look at those things. I think it's very doable and I think we can move forward in that sense. So, I don't know if that helps.

DR. CHESNEY: I think you and Dr. Kauffman have said the same thing, which is to train the caregivers in all the tools they need.

Discuss the labeling tools to help caregivers assess the benefits and side effects. How much detail do you want from the committee on that particular issue?

DR. KELSEY: Well, I guess we're, first of all, looking for agreement that this is a good approach to take, that the caregivers are going to be the ones that are titrating the dose for these patients, and that it's valuable to provide them with material to train them. We'd also be interested in anybody's experience with this sort of thing for other products. We don't have it in our division. But we think that this is a good idea and we assume that you will agree with us on this.

DR. CHESNEY: I think everybody is in agreement that this is a good way to go. Experience. Dr. Fink and then Dr. Szefler.

DR. FINK: We may be saying the same thing. With asthma drugs, there's a very positive trend, which is there's a parent insert with the medication, with the inhaler, the discus, or whatever it is that is written at a 5th or 6th grade level and is totally separate from the package insert. It has no overlap and is educational to the parent but is not the FDA-required package insert. I think you would want something similar that was very parent oriented, 5th, 6th grade level, very straightforward, and not more than maybe a page or two pages in length because no one will read it if it gets too long.

DR. KELSEY: This isn't part of the package insert, but is this an FDA-approved part of the label?

DR. FINK: I don't honestly know the status with the asthma drugs. I think they are parent inserts saying here's how to use the device. They are not technically part of the package insert, and I don't know if they are FDA reviewed or not.

VOICE: They are.

DR. KELSEY: They are. Thank you.

When we talk about labeling, it really extends beyond just the package insert, the container itself and any other things that we've reviewed or included in that.

DR. CHESNEY: Dr. Szefler was next.

DR. SZEFLER: I was going to say, you were asking about partners. I think the potentially obvious partner would be whatever division handles psychoactive medications because you'd want to get some handle on behavioral testing. Motion testing devices. I think you had some questions about adverse effects in terms of activity. There are motion detectors, video assessment type things. So, I think they have the tools because they deal with it in terms of behavior disorders in children. So, you might adapt some of those tools to this type of testing.

DR. CHESNEY: Dr. Danford.

DR. DANFORD: I agree with Dr. Fink's remarks, at least in concept, that having a short 5th to 6th grade level tool to help educate caregivers would be ideal. I think that that might not be practical or realistic in the current problem because I can foresee an insert that's about yea thick with discussions of all of the possible interactions with the various drugs that these individuals are already taking, interactions with other organ systems that are already diseased and troublesome, and finding that it would very quickly become very complicated. The problem is trying to decide where on the spectrum between no guidance and the textbook of developmental disabilities and their pharmacology that we want to settle on the educational insert for caregivers.

DR. CHESNEY: I think probably a lot of that information would come from the studies themselves and how the caregivers could be best taught and how they learn best and so on. Maybe that would come out of the process of studying the drug.

Other comments or questions about labeling?

(No response.)

DR. CHESNEY: I think we can go on to question 4. Dr. Kelsey?

DR. KELSEY: Yes. This has been very helpful, but I agree I think we can move on to the ethical one, number 4.

DR. CHESNEY: So, number 4 is in front of you. Are there additional processes or procedures that need to be in place to ensure the safe and ethical conduct of studies in this special needs population?

Dr. Wilfond, do you want to make any further comments to what you've already made?

DR. WILFOND: I'll make one comment, one addition to my previous comments. I mentioned that the studies that I was envisioning were going to be ones that were offering the individual subjects prospective direct benefit with regards to the regulations. But actually, of course, the PK studies, if they were done separate from a longer-term study, would not count as that, and the interventions for the PK study would also be separate from that. Nevertheless, I don't think those would actually pose any barriers to doing PK studies because I think the risks of those are within the guides of the regulations.

DR. CHESNEY: I think Dr. Walters and then Dr. Goldstein.

DR. WALTERS: This is actually a very interesting test case for the revised Declaration of Helsinki that came out of the meeting in Edinburgh last October. Would we say that a proven prophylactic, diagnostic or therapeutic method exists for the treatment of drooling? If it does, then according to that guideline coming from one medical association, one should not, from this point on, conduct placebo-controlled studies.

DR. GOLDSTEIN: I would offer the opinion that one does not exist that meets the necessary criteria, and therefore, even though I have serious reservations about the use of placebo, it could I think fall within this.

But in terms of question 4, somewhere in the material that was sent to me, the question of institutional review boards and their competency was raised. The members of most institutional review boards have extraordinarily little experience with dealing with these special populations. I would believe that one would need to look very carefully at what requirements would be needed at the institutional review board level to make certain, one, to protect against using other criteria or criteria used in other examples that really don't fit this special population. And that's both a pro and a con. That institutional review board could require certain standards that are really not applicable to this population or might not require enough standards that would be necessary for this population. So, I do respond to the question, will there be a need -- I don't want to suggest that it be parents or not parents, but there will need to be specific expertise on institutional review boards when addressing this particular group of studies.

DR. CHESNEY: That is issue B on the list of questions. Does the FDA have jurisdiction over who should review these studies? Can you tell the company that the review has to include people with expertise in this area?

DR. KELSEY: We can certainly influence companies. To tell you the truth, I'm not sure whether we can absolutely require it, but we can certainly encourage sponsors to go to an IRB that has the appropriate expertise.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: I always love to comment on IRB issues.

Current regulations actually require IRBs to have sufficient expertise to review protocols. If an IRB feels it lacks that expertise, they're under a regulatory requirement to get it. Now, the problem is do they think they lack the expertise.

I think this is a broader issue than simply this population. I would argue that there are IRBs approving protocols for the inclusion of children that lack a pediatrician. So, I think if the FDA wants to step into this, it should. Does it have regulatory authority? it does under ICH E-11. It does under the Good Clinical Practice Guidelines which also specifies that the IRBs are supposed to have expertise. Whether one wants to be more directive about the nature of that expertise would be the question. The regulatory authority is there.

I would agree with the comments. So, it's not a question of understanding. It's a question of appreciation of, in fact, whether that individual IRB lacks that expertise.

DR. CHESNEY: Thank you.

Would anybody on the committee disagree that the FDA should strongly suggest to sponsors that they be sure the IRB has individuals with this kind of expertise on them? Would anybody disagree with that?

DR. WILFOND: I'm not disagreeing but I have another related point that may be a stretch. So, I'm just going to throw this out.

One could consider, for a study like this, having a DSMB. Let me explain why I say that. Not because I think the adverse effects are likely to be so serious that the trial would be stopped during the course of it, but one of the things that DSMBs can do, particularly in the design of a trial, is be a central group to ensure that the safety of a trial is designed in such a way, and that group could have a wide range of expertise outside of the study developers. So, when it got to the IRB, even if you had an IRB that was falling asleep at the wheel, it's not likely they would be approving something that was really going to cause problems.

DR. CHESNEY: Any comments about DSMBs? Dr. Nelson.

DR. NELSON: I think there a good thing. Now, whether you need it in this case, one could -- I guess it would be worth trying to isolate what is it that concerns us about the fact that an IRB may or may not have expertise. Will they approve it for a subset of the population that's inappropriate? For example, a local group home. I mean, really beginning to focus on what is at risk here or not. I guess I'm not as clear about that.

Or will it be that protocols will begin coming out that aren't really well designed, in which case you get in more towards a collaborative group effort. The oncologists have a fairly good system for designing good protocols, and I'm not that worried that an IRB might approve a COG protocol inappropriately. I'm more worried that someone might perform it who can't do it in an investigator sense. So, I think we might want to think through what it is we're trying to prevent or not prevent to happen at the local level, and whether you need a data monitoring committee to fix that would be the question.

DR. CHESNEY: Dr. Szefler.

DR. SZEFLER: I think the DSMB is an intriguing suggestion because I think they serve three purposes. One, they review the protocol again. They look at the body of the people conducting it. Then they also have the privilege of looking at the data as it's evolving. So, if there are any concerns about a product in terms of its safety or performance, they have the ability before the investigators do, and they put some time lines in terms of the company looking at that before you complete the study and then assemble all the data. They will have time tables built in where we would like to see safety and performance and set up some time table of variables. So, it's kind of a monitor that assures that major things or disproportionate things don't go on. So, I think that's an intriguing application.

I think I brought up before I don't know how research is conducted in the special populations in terms of the IRB limitations. A lot of institutions have their own IRBs. Is this one that needs to go to an outside IRB? Is that any kind of ethical concern? So, I don't know how those situations are handled.

DR. FINK: I don't know if IRB is as good as it should be, and I sometimes worry about that. But as I read through the special needs description, it strikes me that it is not at all different from the premature infant, and most academic IRBs routinely consider interventional protocols in premature infants that seem to have all the elements of ethics involved in them in terms of cognitive dysfunction and maybe even in the premature infant, the question of does the parent even speak on the best behalf of the child. So, I'm not sure what makes this really very different from what we're routinely doing in our IRBs that we need to put in special safeguards.

DR. NELSON: I suspect everyone around the table here, though, comes from institutions that have a fairly high pediatric presence and profile. I'm not worried about probably the people around this table. It's a question of what goes on in settings where there wouldn't be that kind of pediatric expertise. Developmental behavioral pediatrics is a very under-represented subspecialty where you may have children with disabilities who are, in fact, in a setting where they don't have much access to that kind of specialty advice or consultation where trials could be conducted without the kind of expertise sitting around this table.

So, I don't think of a pediatric institution or a pediatric rehab institution as being what we're talking about as a best practice standard. It's would you put something in place that could provide a floor that we're talking about.

But I would agree. I don't think I would need much special expertise to do this on our IRB.

DR. CHESNEY: I think we would all strongly support that whatever IRB was involved that there was demonstrated expertise in the care of these children, and if it was something they felt they could address best with a DSMB, then that would be an alternative approach.

Yes, Dr. Walters.

DR. WALTERS: The one area where FDA does currently require DSMBs is in research involving emergency interventions, and that was part of the total package of rules that was passed.

When I was reflecting on ways in which this arena might be similar to and different from, there's not the press of time that there is an emergency situation. On the other hand, there is a spectrum of degrees of competence in the population that will be involved in these studies. So, I actually think that a DSMB for an area that's quite new, rather uncharted territory in pediatrics might be a good additional check and safety mechanism.

DR. CHESNEY: It sounds like our ethical expertise is coming down on the side of DSMBs.

4a. Can I just be sure of what I heard, which is that we do not think that we should restrict this to a subset of patients who can communicate verbally or by keyboard? Is that correct?

And C, should there be independent assessors? I guess we all agreed that the caretakers could be trained and so on. Is there any point at which we feel like there should be independent assessors involved in this process? Dr. Nelson.

DR. NELSON: I guess I heard two separate comments. One was independent; the other was blinded. And we sort of went back and forth at times, but certainly not exclusive. I think if you want to make sure the data you're collecting, particularly where the endpoints involve variable judgment, you're really not questioning the judgment of the parent. Just like a qualitatively study, you usually feel better if you've got two people and you get interrater reliability. Those are the issues you're dealing with. And that wouldn't be for all of your outcome variables. It would just be for those that are more judgment based.

DR. CHESNEY: Dr. Fink.

DR. FINK: I think the interrater reliability is really a key issue here because one parent doesn't want any drooling, a wet chin is a problem, and they're going to be a child like we saw today. Another parent may say if I can put one towel under the child at night and that suffices for the night until 8:00 a.m., that's acceptable. So, there may be very different goals of the different assessors. I'm not sure how you standardize that, but that would be critical because they may have actually very different goals in mind as to what's acceptable outcome.

DR. CHESNEY: That's a good observation because that goes along with what you were saying, which is -- I'm blocking on what it was you said, but they were directly related.

DR. STIEFEL: Definition of the outcome. That's the major issue. And my argument is it doesn't have to be the same. It has to be defined, though, and then determine whether or not there is an outcome.

DR. CHESNEY: Right, thank you. That was it precisely.

Dr. Wilfond.

DR. WILFOND: I think that it's possible even if different parents have different desired outcomes, they still might be able to reliably make an observation about whether or not the chin was dry or whether or not they had to put a towel under the neck. That's really what our question is. Can we obtain reliable observations on what's occurring? Then later on we can decide what's the appropriate goal that would count as being as efficacious.

DR. CHESNEY: That's a good point.

Dr. Stiefel.

DR. STIEFEL: Sorry. I have to be brief, but I also have to bring in the other thing that we practically are running into, which is tied into IRB, but not necessarily related to. But it comes back to the human services, human rights issues that I addressed earlier. We're actually at the point where studies get stopped and slowed down, particularly for kids that receive both federal and state funds through the state agencies of disabilities. They again have not IRB but have human rights issues that have to be addressed, and we find that if there's not synergy between the IRBs at our centers -- back to your comments, we always have that tension of competency and representation and other things. But most of the major centers are looking at that. It's the other issues that are there. There's a long history of abuse, sterilization.

This is really, truly a distinct special needs population that we're seeing here, and those rights cannot be and the history cannot be separated from what's going on at this point. We have found that actually we do all the other things, have similar sorts of things in regards to the DSMBs and other things in place, and then get shut down by not having worked with the human rights folks.

So, it's something you just need to be aware of, not that it's your job to fix that, but to be aware of that in the process. As you put up each hurdle that we have to go through to be able to do studies, there is extraordinary disincentive to ever go through that. And that's an issue.

DR. CHESNEY: Could you clarify that a little bit? How does one go about finding out who is responsible for human rights as you were referring to them?

DR. STIEFEL: Well, let me make it personal. I'm the medical director for our state human rights agency, and I didn't think about it, in terms of our studies, that I ever needed to run those by human rights even though I know that that's there and I sit on the human rights committee. We just assumed if we went through the university IRB process that that would be sufficient. That was a very incorrect, naive, and also disrespectful assumption on my part.

So, I don't think people do know. Again, I think it's something that comes out usually in retrospect. People are involved in studies and then these issues are raised either by a parent or by a consumer or someone else, and then it has to be addressed retrospectively. So, it's a huge issue, and I don't think there is any standard.

If you look at it state by state, these are different regulations depending upon whether or not the disability service is part of mental health or part of other sorts of things. There is no standard across the country. So, other than saying people who are involved in research in these areas need to be respectful and conscious of this and find out what their local climate and culture is, I don't know what to say beyond that other than that needs to happen. And I am the person who should have known that the best and it happened.

DR. CHESNEY: So, it would be your state disability office or?

DR. STIEFEL: I'm assuming that, but again remember that that doesn't always exist in all states. Sometimes the mental health and disability are combined. So, it's not just a general thing, but there usually is something at the state level in terms of accountability. Remember, though, many times those things trickle down from federal sort of mandates, which I don't know the specific regulations. But we should probably define that as part of our opinion.

DR. CHESNEY: Would that be important only if you were considering enrolling children in a state funded institution, or if you had all private patients, it would still be an issue?

DR. STIEFEL: Most of my private patients receive respite, other sorts of resources from things that are both entitlements and not entitlements that come through Medicaid super waivers. Again, it's the Medicaid super waiver part that then allows for these kind of things to come into issue.

DR. CHESNEY: Has the Academy ever written a statement on this type of issue, which is how do you get through all the hurdles that are out there for doing research on children with disabilities? It seems like that might be a statement to consider for the section.

DR. STIEFEL: I will take that back to the section. I have to be honest and say I don't know. I can bring that back to the group at a later date.

The American Academy of Child and Adolescent Psychiatry, again talking about that interface, and the American Psychiatric Association have put out guidelines, along with HCFA guidelines, which were updated. So, people have put out guidelines for basic sort of research and basic sort of need to serve this underserved population.

But specifically to what you're talking about, I haven't read anything coherent and cohesive enough to be able to do that, not that that doesn't exist. But I will get that information back to the committee as appropriate.

DR. CHESNEY: Dr. Walters.

DR. WALTERS: I'm trying to think for a moment outside the box of our mandate. I'm wondering whether there are going to be parallel studies conducted in adults while these studies in children are being done, or whether there's any particular reason why it wouldn't be a good idea to be conducting studies in adults at the same time that the studies in children are going forward.

DR. STIEFEL: This is more complex because in developmental disabilities we follow the education system which provides services up to 22 years of age, and most medical services geared around that transition to adult systems are very problematic. I actually agree with you. It's beyond this committee obviously, but these things also need to be studied in adults, for the record.

DR. CHESNEY: Dr. Kauffman.

DR. KAUFFMAN: Just a quick answer to your question about guidelines. The Academy of Pediatrics guidelines on ethical guidelines for studies in children from the Committee on Drugs has a section on vulnerable populations. It's fairly general, but it does address the essential issues that one needs to bring into play when you're dealing with especially vulnerable populations. I'd refer folks to that too.

DR. CHESNEY: Thank you.

Dr. Kelsey, how are we doing?

DR. KELSEY: I'd say great. I feel like you've worked hard for us today, and we've learned a lot. I appreciate the comments and the time that you've taken to help us with this. As far as I'm concerned, we've gotten a lot of information and the questions have been adequately answered. So, unless anybody else has anything to say, I feel like you've done your job.

DR. CHESNEY: If no one else has any comments, Dr. Murphy, did you want to make any closing remarks?

DR. MURPHY: Thank you.

DR. CHESNEY: Thank you, Dr. Murphy. Really nothing else?

DR. MURPHY: Really nothing.

DR. CHESNEY: Dr. Hudak had a question and then I have something to tell you about. Then I think we're done. Dr. Hudak.

DR. HUDAK: Dr. Murphy or Dr. Kelsey, Dr. Mathis, it's been a very good conversation today. A lot of intriguing ideas back and forth. I think I speak for a lot of members of the committee. We come to these discussions, we exchange a lot of information, and then at least I don't get a whole lot of follow-up as to where it goes after that. I understand there might be some constraints in terms of what information can be shared back.

But could you tell us what is the next step the FDA is going to take on this? Is it going to be as a request to a drug company or drug companies to provide new formulations, to conduct further research? Where is this going to go on a practical level?

DR. KELSEY: Well, of course, we can't talk a lot about specific interests and that sort of thing, but I can tell you that I didn't just wake up in the middle of the night one night and say, gee, this is an issue that I think that we should go and ask an advisory committee about. So, we have come to you because some questions have been raised, and we're trying to get ahead of the curve, if you will, and get your advice, try to define the issues so that as the process moves forward, we will be well prepared to help sponsors that are interested in developing these products to design their trials well, and we'll be comfortable that we've covered the ethical as well as the design issues when we give the advice.

I don't have specific plans about promulgating the transcript of this meeting, but that's certainly something that we can think about doing to get the word out to the research community that we are interested in this sort of thing.

DR. CHESNEY: Dr. Murphy.

DR. MURPHY: Again, whenever we bring a general topic, we usually do try to develop some consensus statement. With the ethical issues particularly we have tried to do that.

It does have impact. Maybe you all don't see it in your daily work, but we see it because we don't have people submitting PK studies done in East Europe on children who aren't going to derive direct benefit, which we were seeing, because we will not accept that data. It's not that we won't accept data. I've been told I can't say that. We will definitely accept the data, but we will not use it to grant exclusivity.

So, the issue of what do we do with this. I think you bring up a very good point. We try to provide feedback in the way of the consensus statements as to what we think the committee said. Those do go up on the Web, and even if you're not assiduously scrolling through the FDA website, the companies are.

You don't have a specific product coming out of this committee like you do many others. So, you sort of know what happens from a product.

So, if we have a better way, if there is some sort of additional process that the committee would like to consider undertaking, we could take that issue back to the Advisors and Consultants staff in the FDA as far as is there anything else we could do because the transcripts are made available. They are public, and that is something we do, again, provide the public.

DR. HUDAK: I think the one observation that I would make -- I think, again, I speak on behalf of the committee -- is that we have very general discussions, very broad issues. I think that's one thing the committee does and I think does well.

I think the other opportunity for the committee or subcommittee or whatever might be -- and, again, I don't know what the legal constraints on this are. But when these things do percolate back with specific -- you send out specific requests. You get back specific proposals. In terms of reviewing those specific proposals, because I think a lot of us have expertise with the actual trial design, statistics, implementation, those sort of issues that we work with on a daily basis, if the FDA is ever in need of having that sort of input from an external committee, I think this committee would be a logical choice to bring that up before.

DR. MURPHY: I think because we are dealing with the implementation of the exclusivity and rules, we don't have an approval product, and that is very specific questions about that product that we would bring. It doesn't mean we won't have for the future, but we're sort of building our infrastructure right now.

The other thing, just to remind you guys, is you did contribute, as I pointed out, to the fact that we don't ask for studies to be done for sleep disorders. So, that's on the waiver list.

In our updates, we try to point out the impact of your discussions, but I'll try to make sure we follow up with you on the hepatitis C, if we issue any written requests or the types of trials that we end up asking for, and the same thing in this area in the future.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: Perhaps an area where we could be specifically helpful in terms of specifics is to review publicly available templates that the FDA has that are public information on the website to see that they are pediatric friendly if not pediatric specific.

DR. MURPHY: We could do that, but you have to realize that we also have another body of experts, the adult hypertensive people or the adult oncologists. Some of these have already gone through some of those groups too. So, we tried to get certainly the pediatric people and the oncology people together. If you have templates that you think we should review, we have to combine the sessions with the other body of experts. That's all I'm saying. So, we try to do that.

DR. GORMAN: I guess I wasn't so much suggesting that we change the total focus of any template, but more just look at the specifics that pediatric IRBs and researchers might have difficulties with.

DR. MURPHY: Okay. If you guys have particular points or concerns that you would like discussed -- that's one of the reasons we are consulting you -- we'd like to know what they are, and we will put together a meeting on it. What we'll probably do, if we get a lot of them, is we'll probably put them together and send them back to you and say, you're going to have to prioritize them, or we'll prioritize them and say, do you agree with our prioritization? That would be great. I want to indicate we think that's part of the role of this committee is to help us develop these areas. So, if there are specific points that you want brought forth, let us know. Communicate through Jayne.

DR. FINK: I guess a question. Today clearly we identified that there's this fairly large population. There's a poorly understood issue of drooling, upper airway function, sleep disorders. It would seem like some communication with groups like MCH or NIH, that this is an area that's been identified where additional research would be highly desirable, would be a nice outcome.

DR. MURPHY: Yes. Actually I will just come out and say the level of the discussion has been so good and the participation externally so poor -- I'm very disappointed in the public participation -- that we do need to find a way of including. Maybe we need to do a better job of letting people know about these meetings. I'm sure everybody doesn't read the Federal Register. It's just been a tremendous disappointment considering the discussion, the number of people who heard it. I think that is one thing we need to look at.

We have a problem because we can't notify one group and not every other group. So, if we notify somebody, we have to make sure we notify everybody.

Yes, sir.

DR. GOLDSTEIN: I've just come from two days of meetings at NIH in which an inter-institute NIH task force was reviewing the status of information leading up to the potential development of trials on spasticity, rigidity, and dystonia. There's a reasonable probability that this NIH inter-institute task force -- and it's child health, neurology particularly -- will become a working task force.

In following up one of the suggestions that was made, I think it might be extremely valuable to that group and to the FDA to begin to share some information about this conversation because if that group, in fact, decided with NIH funding to do a multi-institutional trial and developed the protocols, et cetera, I think it would answer a fair number of the problems rather than relying completely upon industry to develop the background on this. It's just fortuitous that within one week two separate PHS agencies are addressing similar kinds of issues. And that would be an operational unit. So, I would urge you to consider discussing, even informally with that group, the possibility of it undertaking this as an area of priority research.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: It's a quick question and then a reinterpretation to make sure I heard you.

Are all the templates on the Web? I know a number of them are, but is that the complete list of currently developed templates?

DR. MURPHY: Yes. There are only a limited number of templates. If we have not developed a template, it is either because the diversity of the products for that disease were such that we did not think we could apply a template or that the level of knowledge was so different amongst the classes that we felt we could not apply a template, or that we just haven't had enough activity in that area to develop a template. So, there are numerous reasons why there may not be one.

DR. NELSON: Perhaps it might be part of the Academy's recommendations that written requests, for example, could be a public document, but at the very least, templates are and that would be one arena. But basically your response to Rich was go to the website and read them. If you think there are some issues there, that we can then communicate that back to Jayne and to Joan as a way of suggesting future agenda items.

DR. MURPHY: Right.

And just one follow-up on one statement. We do, again, make efforts to coordinate with other Public Health agencies. As you've heard, there are really only three of us -- well, two people who work at this full-time on pediatrics, and it's a matter of trying to learn all the other players and get everybody involved. Dr. Rodriguez has just joined us in the past year as our science director. So, I get to turn to him and say that he can help us develop some of this liaison. He's already very active and participating with the PPRUs and bringing back some of the development issues that they have, dealing with other agencies. So, we will continue to improve in developing those liaisons.

But I would request the opposite too, which is if people know of experts in the field in other agencies, please send them to us. My e-mail address is murphyd and Bill is rodriguezw@cder.fda.gov. We will then try and connect up with them. We did a lot with NIMH on the development of neuropsych. We've done a lot with NCI with the development of cancer products, oncologic products for children. So, we know there's a lot more to be done, and if you have experts that we could develop relationships with, please do forward that information to us.

DR. CHESNEY: Dianne, one thing that I think came out a little bit yesterday and that you heard a little bit today is that the committee would like to feel maybe a little more involved in general issues, and the template discussion is one of those. Rather than just coming to talk about hepatitis C or drooling, maybe we can support again your efforts by looking at broader issues. You mentioned a separate meeting where maybe we just talk about templates or some of the other issues that come before all of you that we might help with. It occurs to me that maybe having somebody from the NICHD -- I don't know if there's anybody within the NIH like yourself that coordinates all of these pediatric studies, but if there was or if they maybe should create one so that we don't duplicate efforts and do know what everybody is doing, maybe that would be an appropriate time to have that person come.

But overall, again, I think we would all like to just say what an incredible job you all have done. It's just overwhelming. I don't know if you all know that Dianne is also in charge of bioterrorism and antibiotic resistance, any one of which would take a staff of 50.

(Laughter.)

DR. MURPHY: And antimicrobial development. Just don't forget that one, too.

DR. CHESNEY: And you were in charge when there wasn't enough penicillin or chloramphenicol -- I forget.

DR. MURPHY: Drug shortages. That plus pregnancy are also in my office.

DR. CHESNEY: Pregnancy and drug shortages as well.

So, I guess we're willing to help you in any way that we can, but we all emphasize what a tremendous job you've done. Whatever we can do to help support the congressional hearings next month and then obviously to get FDAMA passed again.

For this particular session, I really wanted to thank our speakers tremendously for taking the time in coming and for Dr. Kelsey and Dr. Mathis for finding you and for outlining the issues. It's always so impressive to me how much I don't know. I don't know why that should be impressive, but I've just learned a tremendous amount here today. You all did just a superb job of just presenting the issues and making it all very clear. So, I think it was fun for us.

I particularly want to acknowledge Jayne Peterson who puts all of this together, including a seating chart so I always know who is where and deciding to do everything right. So, thank you very much, Jayne.

And thank you to all the committee members. We all learned, I hope, so much from each other. And our invaluable consultants.

Any other comments?

Jayne wanted me to remind you that the handout you got you'll see is the Federal Register of Tuesday, April 24th, which is the Subpart D that just came out today. So, you are the first to see that unless somebody was combing the Web this morning.

Thank you very much.

(Whereupon, at 12:55 p.m., the subcommittee was adjourned.)