+ + +


+ + +


+ + +


+ + +


JUNE 11, 2002

+ + +

The Subcommittee met in the Versailles Room of the Holiday Inn, 8120 Wisconsin venue, Bethesda, Maryland, at 8:00 a.m., Joan P. Chesney, M.D., Chairperson, presiding.


JOAN P. CHESNEY, M.D., Chairperson

THOMAS H. PEREZ, R.Ph., M.P.H., Executive Sec.



PRESENT (Continued):






















ALSO PRESENT (Continued):















Introduction, Joan P. Chesney, M.D. 6

Meeting Statement, Thomas H. Perez, R.Ph. 11

Opening Comments, Dianne Murphy, M.D. 16

Introduction to the PPI Written Request Template,

Hugo Gallo-Torres, M.D. 20

Pathologic Pediatric GER and Clinical Trial

Design, Eric Hassall, M.D. 31

Clinical Trial Design, Mark Hudak, M.D. 47

Ethical Issues, Benjamin Wilfond, M.D. 67

Open Public Hearing:

Jerry Gardener, M.D. 78

Dr. Greg Kerns 82

Introduction to Questions and Charge to the

Subcommittee, Dr. Victor Raczkowski 101

Subcommittee Discussion of Questions 106

Preliminary Priority List of Drugs:

Introduction, Dr. Anne willoughby 239

Background, Dr. Rosemary Roberts 242

Development, Dr. William Rodriguez 258

NIH's Role, Dr. Anne Willoughby 263

Discussion, Dr. Dianne Murphy 267






Open Public Hearing:

Martha Hellander, J.D. 280

Presentation of Questions and Goals for

Discussion 296

Update from Europe:

Dr. Julia Dunne 381

Dr. Agnes St. Raymond 395

Update by Dr. Dianne Murphy 414

Rule and Exclusivity Update 425



(8:12 a.m.)

CHAIRPERSON CHESNEY: Good morning, and my name is Joan Chesney, and I'd like to welcome everyone to this morning's session on the use of proton pump inhibitors for gastroesophageal reflux disease in children.

The uses of these agents without appropriate labeling has increased over the last few years, and particularly in infants under one year of age. The agency has developed a template for pharmaceutical agents to help direct their studies for these agents, and the questions for us this morning are basically threefold.

The first one has to do with whether efficacy studies should be considered for infants under one year of age because gastroesophageal reflux disease in infants manifests itself generally with respiratory in supraesophageal symptoms as opposed to those symptoms in older children.

And, secondly, their question for the committee is that if the committee agrees with the concept of efficacy studies in infants under one year of age, are the randomized withdrawal design studies they've proposed acceptable, and what should the endpoints be?

And, thirdly, are the PK and PD studies recommended for children over one years of age appropriate?

So with those introductory comments, I did want to thank the group that put together all of the references for the committee, which I thought were very appropriate and focused, and for those of us not in the area, it would have taken weeks of work to identify these papers.

So let me start then by asking if we could go around the room and have everybody introduce themselves, and maybe I'll start with Dianne.

DR. MURPHY: I'm Dianne Murphy, and I'm the office director of the For Now, and we'll talk a bit more about this later, Office of Pediatric Drug Development and Program Initiatives.

DR. RACZKOWSKI: Good morning. I'm Victor Raczkowski. I'm the Acting Director of the Division of Gastrointestinal and Coagulation Drug Products, the division that put together the proton pump inhibitor template.

DR. BIRENBAUM: Good morning. I'm Deborah Birenbaum. I'm medical team leader for the new Division of Pediatric Drug Development and one of the medical officers who consulted on this project.

DR. GALLO-TORRES: Good morning. Hug Gallo-Torres. I am a medical team leader in the Gastrointestinal Coagulation and Drug Product Division.

DR. O'FALLON: Judith O'Fallon, biostatistician at the Mayo Cancer Center.

DR. LUBAN: Naomi Luban. I'm Vice Chair of Laboratory Medicine and Pathology at Children's Hospital National Medical Center, George Washington University.

DR. GORMAN: Richard Gorman, pediatrician in private practice in Ellicott City, Maryland.

DR. FINK: Bob Fink, pediatric pulmonologist, Washington, D.C.

DR. DANFORD: David Danford, pediatric cardiologist, Omaha, Nebraska.

DR. SANTANA: Victor Santana, pediatric oncologist, St. Jude's Children's Research Hospital in Memphis, Tennessee, and the University of Tennessee.

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

CHAIRPERSON CHESNEY: Joan Chesney, pediatric infectious disease, the University of Tennessee Health Science Center in Memphis.

DR. PEREZ: Tom Perez, Executive Secretary to this meeting.

DR. EBERT: Steve Ebert, a clinical pharmacist in infectious diseases at Meritor Hospital and Professor of Pharmacy, University of Wisconsin, Madison.

MR. HUDAK: Mark Hudak, a neonatologist at University of Florida, Jacksonville.

DR. HASSALL: Good morning. Eric Hassall, pediatric gastroenterologist, Vancouver, British Columbia.

DR. FERRY: I'm George Ferry, a pediatric gastroenterologist at Baylor College of Medicine in Houston, Texas.

DR. GOLD: I am Ben Gold, a pediatric gastroenterology, Emory University in Atlanta, and the Director of the Helicobacter Lab at Centers for Disease Control in Atlanta.

DR. KAUFFMAN: I'm Ralph Kauffman. I'm Director of Medical Research at Children's Hospital in Kansas City, Missouri, at the University of Missouri. I am here partly representing the Academy of Pediatrics.

DR. WILFOND: I'm Ben Wilfond, a pediatric pulmonologist with the National Human Genome Research Institute and also with the Department of Clinical Bioethics at the NIH.

DR. WARD: I'm Bob Ward, a neonatologist, University of Utah.

DR. BLACKMON: Lillian Blackmon. I'm a neonatologist recently retired from University of Maryland, and I'm partially here APP Chair, Committee on Fetus and Newborn.

DR. WINTER: Harland Winter, a pediatric gastroenterologist, Mass. General Hospital for Children in Boston.

DR. JAMES: Laura James. I'm a pediatric pharmacologist at Arkansas Children's Hospital in Little Rock, Arkansas.

DR. SPIELBERG: And Steven Spielberg, Pediatric Drug Development at Johnson & Johnson, representing PHRMA.

CHAIRPERSON CHESNEY: Thank you, and we'll let Tom Perez give the meeting statement next.

DR. PEREZ: Thank you.

Good morning. The following announcement addresses the issue of conflict of interest with respect to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.

The Food and Drug Administration has prepared general matters waivers for the following special government employees which permits them to participate in today's discussion: Dr. George Ferry, Dr. Robert Fink, Dr. Richard Gorman, Dr. Eric Hassall, Dr. Naomi Luban, and Dr. Victor Santana.

A copy of the waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12A30 of the Parklawn Building.

The topics of today's meeting are issues of broad applicability. Unlike issues before a committee in which a particular product is discussed, issues of broader applicability involve many industrial sponsors and academic institutions.

The committee members have been screened for their financial interests as they may apply to the general topics at hand. Because general topics impact so many institutions, it is not prudent to recite all potential conflicts of interest as they apply to each number.

FDA acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussion before the committee, these potential conflicts are mitigated.

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

Dr. Lillian Blackmon is participating as an expert in neonatology and is not representing the opinions of the National American Academy of Pediatrics Committee on Fetus and Newborn.

Dr. Benjamin Gold received speaker fees from TAP Pharmaceutical, AstraZeneca, and ASAI. He is also a scientific advisor to TAP Pharmaceutical, Wyeth AstraZeneca, and ASAI.

Dr. Laura James is a co-investigator on a Wyeth-Ayers sponsored study of the pharmacokinetics, pharmacodynamics, safety and tolerability of intravenous pantoprazole in hospitalized pediatric patients. She is consulting with AstraZeneca concerning the development of a pediatric esometrazole program.

I forgot my glasses.

Dr. Agnes St. Raymond is a full-time employee of the European regulatory authority, European Medicines Evaluation Agency. She deals with pre-licensing activities of medicinal products.

Dr. Steven Spielberg is Vice President, Pediatric Drug Development at Johnson & Johnson.

Dr. Robert Ward is a co-investigator for Abbotts Ross Products Division. He also receives consulting fees from Wyeth-Ayerst, McNeil Consumer Healthcare, Janssen Research Foundation, and ZARS, Incorporated.

Dr. Harland Winter is an officer of the Children's Health and Nutrition Foundation; is negotiating support for an educational program with TAP, Wyeth, AstraZeneca, Janssen, Proctor & Gamble, and Olympus. Dr. Winter previously completed research trials for AstraZeneca, Janssen, Proctor & Gamble, TAP, Reliant Pharmaceuticals, Celltech and Centicore. He is currently an investigator on trials for TAP, Centicore, and Proctor & Gamble.

Dr. Winter also consults for AstraZeneca, TAP, and Janssen. Additionally, he is a member of the Speakers Bureau for Proctor & Gamble, and receives speaker fees from Centicore.

Further, he is a scientific advisor to AstraZeneca, TAP, and Janssen.

Dr. Ralph Kauffman is currently involved in research studies for Janssen, Bristol-Myers, Squibb, and Merck. He is also a scientific advisory for McNeil Consumer Products, Johnson & Johnson, and Purdue Pharma.

Dr. Walkup has contracts grants from Eli Lilly, Wyeth-Ayers, Solvay, and Pfizer. He also receives speaker fees from GlaxoSmithKline, Solvay, and Janssen.

In the event that the discussions involve any other products or firms not already on the agenda for which FDA participants have a financial interest, the participants' 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 financial involvement with any firm whose product they may wish to comment upon.

That concludes the meeting statement.

I'd also like to make a couple of announcements. One, these microphones are on all the time. So they will pick up whatever discussions you're having. So everything will be on the record.

Okay. In addition, the agenda that has been passed out, there are two words that made it onto the agenda that should have been stricken. At the very top, GERD template. I apologize to anyone who thought we were not coming back from lunch. We must kill any rumors that FDA only works half days. So this is going to be a long day.

Thank you.


And now Dr. Murphy is going to make opening comments.

DR. MURPHY: Yes. Thank you.

First of all, I would like to welcome back -- it's delightful to see the Pediatric Advisory Subcommittee as you enter into your fifth year of providing advice and guidance to the agency. That's a pretty exciting statement, I think, that we are now in the situation in which we have enough issues to discuss pediatric drug development on at least an annual basis. And as you well know, we anticipate that you will be meeting more frequently in the future.

With the passage of the Better Pharmaceuticals for Children Act, which we will speak more about tomorrow as the subcommittee will be participating in a training session on that. So we will be focusing today on the result of what we are glad to say is an evolutionary process that we're seeing as we are able to ask for studies to be conducted in children, learn from the science that is evolving, and come back and seek additional input and advice.

We have always said that we anticipate this whole process will be one in which we learn, and we will need to reevaluate what we've learned, and to then restructure how we proceed in asking for additional studies.

And the package that the division has put together this morning for you reflects that progress and evolution, and it's actually quite exciting to be able to do this at this point.

I think the other point about the discussion this morning is that we usually have at least a half day of ethical issues for this committee. We have not neglected that. I'm sure you're aware if you read your package that there are ethical issues to be discussed in the trial designs that are being brought to you today.

So you have a very full day. When I saw the questions the division had developed I thought we really needed to extend the agenda to about eight o'clock tonight, but I know Joan will keep you guys on track and keep you moving because you have a tremendous amount of work.

So I'm not going to say too much more, except to say that the rest of today we are then going to bring to you one of the new tasks that you have been asked to participate in, which is the development of work with the National Institutes of Health and the FDA in developing a process for a priority list of products to be studied, and these products need to be off patent.

For the rest of the day when we say off patent, we're going to be referring to both off patent and those products without any remaining exclusivity, just to shorten the verbiage.

And we are also very pleased today to have our guests from Europe. We've worked extensively -- the agency has -- with many of the regulators in Europe to be able to move forward on a global manner of the development of products for children, and they are going to update you on the progress that is being made in Europe. And I think that will be very interesting for the committee to hear.

It's a very different process. If we think our lives are complicated, wait until you hear about theirs.

And I will end right there except to again say that we wish to thank everybody for being here, committing their time, their effort. I think that the agency benefits tremendously from the discussions, and I know the science of our trial development benefits from these discussions, as does the thoughtfulness of the ethical discussions.

And we look forward to the rest of the day.

Thank you.

CHAIRPERSON CHESNEY: Thank you, Dr. Murphy.

We have a lot to do this morning, and I'd like to ask if you could hold questions for the speakers until just before the break. If we don't have anybody speaking in the open public hearing, we'll have a half hour there, and if we do have somebody, we still may have some extra time there.

So if we could start with Dr. Hugo Gallo-Torres talking about an introduction to the proton pump inhibitors, the written request template.

DR. GALLO-TORRES: Good morning. Thank you for the opportunity. This is a very exciting occasion, indeed, particularly for the opportunity of introducing the theme of conversation/interaction today.

My name is Dr. Hugo Gallo-Torres. I am a medical team leader of the Gastrointestinal Coagulation Division.

This is an outline of the topics I'm going to be briefly mentioning. These titles and some titles will show up in the next slides.

It is important as an introductory statement to say that the pediatric written request is a voluntary program -- sponsors do not have to do it -- that provides financial incentives to companies for conducting needed studies of drugs that may produce a health benefit to the pediatric population.

The PPI template for written requests is used in the treatment of gastroesophageal reflux disease, GERD. As part of the rationale, I would like to simply say a couple of things.

Information relating to the use of PPIs may produce a meaningful health benefit in the treatment of GERD, as we said, in the pediatric population. Please note that we have chosen GERD because this is more prevalent than other indications, such as duodenal ulcer, gastric ulcer, and so on.

We also know that proton pump inhibitors are widely used in pediatric patients, and we know this from published treatment algorithms for pediatric patients with GERD, and we also know this from the usage data available, such as the IMS health data provided to you in the briefing document.

Two points regarding the extrapolation of efficacy data. FDA regulations permit extrapolation of adult efficacy data to pediatric patients when? When there is similar course of the disease in adults and pediatric patients and when there is similar drug effects in adults and pediatric patients.

Of course, all of the information supporting pediatric use also is needed.

What I'm going to do next is to contrast the two main age groups, that is, those who are less than one years of age and those who are one year of age or older.

The course of GERD in adults, we believe, is not sufficiently similar to the course of pathological gastroesophageal reflux in this group to permit extrapolation for the adult efficacy data. Therefore, the PPI template does require, does request efficacy studies in this pediatric patient group.

In the one year old group, the course of GERD is sufficiently similar to the course of GERD in adults to permit extrapolation of efficacy. Therefore, the PPI template does not request efficacy studies in this pediatric age group.

This is a table of the requested studies by age group, and you can see that the studies go all the way from neonates and pre-term infants to pediatric patients 16 years of age.

You also notice that thick line here separates the studies in patients who are less than 20 months of age versus those who are older.

Listed here are the components of the different studies: pharmacokinetics, single and repeat dose; pharmacodynamics; exposures and response; efficacy, and safety.

You notice that pharmacokinetic studies are requested throughout for all the studies, and so are safety studies. So these are dissimilarities that will not be stressed any longer.

What I'd really like to do is to mention the dissimilarities, especially the pharmacodynamic and the efficacy components. As you can see from this table, the PPI template requests the pharmacodynamic studies in this group and in this group, but not in children who are one year old or elder.

And the main reason to do is because we believe that data from adults can be extrapolated to this group of patients.

Similarly, the template requests former efficacy studies. These studies are to be powered for efficacy in these two groups of patients, but not in these for the same reason.

What I would like to do next is to briefly discuss selective individual studies by age group, and here the handout provided to you has a lot of these statements. So I will not repeat some of them. They will just show up in the slide.

In the 12 years to 16 years of age, Study 6, there is a pharmacokinetic and safety component. The patient population is patients who have a clinical diagnosis of suspected GERD. The PK component is a randomized pharmacokinetic safety study of at least two levels of the proton pump inhibitor for single and repeated dose. Either traditional or population PK analysis can be used, and repeated dose of PPI levels are selected on the basis of results from the PK component.

Study 6 has an eight week safety component of at least 100 patients. This is a multi-center, open label, nonrandomized, eight weeks in duration study.

Next one, please.

In the one year to 11 years of age group, the PPI template requests Study 5, and this is a pharmacokinetic exposure response and safety study. The patient population consists of patients with endoscopically proven GERD. The exposure response and safety component where we request at least 80 patients, 40 of these in the one to five year and 40 in the six to 11 years of age, a more or less representation of the different age groups. It is randomized, double blind, dose ranging with eight-week treatment.

It is very important to stress that this study is exposure response study. It's not powered for efficacy.

In the one month to 11 month of age of Study 3, we have a pharmacokinetic, pharmacodynamic and safety study. The study population, and this is Study 3, are hospitalized patients, candidates for acid suppressive therapy because of a presumptive diagnosis of GERD.

There's a pharmacodynamic and safety component to this study randomized at least to those levels of the PPI. Changes in intragastric and/or intraesophageal pH are requested. Pharmacodynamic assessments in patients that require tube placement or pH monitoring for clinical management is requested.

It's important to point out that the tube placement is not done for the purpose of the study. It's not necessarily related to the protocol.

In Study 4, efficacy and safety study, the patient characteristics are those of clinical diagnosis of suspected GERD. It is important to point out here that acute, life threatening events due to GERD are excluded in Study 4.

And it is also important to point out that resource tests used to establish the diagnosis will be provided, even though the test may not support the so-called diagnosis of suspected GERD.

In the one months to 11 months of age, we also have a Study 4, and all I'm going to say here is that there are several publication provided to you, especially from Dr. Temple, addressing the advantages and disadvantages of using the treatment of withdrawal design.

What I should like to do is to stress certain issues related to the design. The endpoints in Study 4 are supraesophageal and airway complications associated with GERD; GERD signs and symptoms; growth parameters; frequency, severity, and duration of wheezing; and assessment of compliance.

Study 4 is powered for efficacy, and we have now arrived to what we believe is probably the most interesting type of studies, those studies in neonates and pre-term infants with a corrected age less than 44 weeks.

And here we have two studies, one and two. Study 1 is a pharmacokinetic/pharmacodynamic and safety evaluation. Who are the patients in this study? The patients in this study are monitored patients admitted to a newborn intensive care unit or a special are nursery who have evidence of obstructive apnea, who are candidates for acid suppressive therapy to treat a presumptive diagnosis of GERD, and whose body weight is at least 800 grams.

This pharmacodynamic component is not too dissimilar from the one we saw in the one to 11 months age group. Excuse me, please.

There's a safety component to Study 1. Apnea and bradycardia are assessed concurrent to pH metric.

Study 2 is an efficacy and safety study. The patient characteristics are the same as for Study 1. Again, you have already seen or heard the design of Study 4 for pediatric patients one to 11 months of age.

In Study 2 the outcome measures are different, and rather than going through this information that we already mentioned, I would like to stress certain aspects of the design of Study 2, and here they are.

Study 2 is stratified for methylxanthine and corrected by age. In this study it's important to consider whether the patient is receiving concomitant prokinetic agents, such as metoclopramide or erythromycin, theophylline agonist (phonetic). The patient, of course, may very well need these medications, but these medications may be confounders. So we need to take this also into consideration.

This is a very important point to stress. Patient enrollment and efficacy is measured by obstructive apnea, and obstructive apnea is assessed by pneumograms.

I should also like to mention that additional outcome measures in the Study 2, and these include patient discontinuations due to ineffective treatment, apnea as assessed by conventional cardiorespiratory monitoring, and nursing observations, and severity of apneic episodes.

Study 2 is powered for efficacy.

Then I'd like to mention additional safety measures, such as listed in there: overall mortality, adverse events, including co-morbidities of prematurity and growth.

The withdrawal phase of Study 2 is important because the protocol will define discontinuation criteria due to adverse events or insufficient therapeutic effect, in other words, treatment failure.

And therapy for central apnea should be dropped. There's a long-term safety component to Study 2.

So we have now arrived to the overall summary, and it is important for us to rate the following.

Number one, adult efficacy data cannot be extrapolated to pediatric patients less than one year of age.

Number two, efficacy of proton pump inhibitors in the treatment of gastroesophageal reflux disease in pediatric patients less than one year of age must be established in adequate and well controlled clinical studies briefly summarized for you here.

Number three, we believe that the randomized withdrawal design can minimize prolonged exposure to placebo in situations where inclusion of a placebo arm may be felt to be undesirable or not feasible.

Number four, the written request has provisions for prompt discontinuation from randomized study therapy when discontinuation is felt to be clinically appropriate.

Number five, for pediatric patients more than one year of age, the efficacy of the proton pump inhibitor in the treatment of GERD may be extrapolated from efficacy studies in adults.

And, finally, for all pediatric populations, adequate pharmacokinetic and safety information is needed.

Thank you very much for your attention.

CHAIRPERSON CHESNEY: Thank you, Dr. Gallo-Torres.

And our next speaker is Dr. Eric Hassall, who will be speaking about pathologic pediatric gastroesophageal reflux and clinical trial design, differences between infants under one and over one year of age.

DR. HASSALL: Good morning, everybody. Thank you very much for the opportunity to speak on this topic today.

This is what I'm going to talk about. The outline, a little bit of background; the difficulties in doing pediatric clinical studies; a couple of definitions; brief mention of complications and goals of treatment; mention of prevalence and natural history in different age groups; available treatments; a little bit about pathophysiology mechanisms; etiologies; acid secretions; underlying diseases; a brief mention of pharmacokinetics; focus really for a little bit on endpoints; feasibility; and for my own view of what the requirements are for performance of a successful study.

The difficulties in doing pediatric studies are as follows. I'm not going to address the ethical issues because one of the other speakers is going to do that.

Of course, we know that there are age related differences in disease manifestations.

The fears of parents, the fears of investigators.

Feasibility; what's practicable in various age groups.

The time and labor intensiveness of dealing with children and their families is something definitely to be reckoned with.

The need for flexibility. There may be some studies in which certain tests might need to be options. Certainly in one of our other studies we built one of those, that flexibility in.

And the inexperience of pediatric centers. As you know, the recent push for doing studies in children will lead to some enormous benefits, but at the present time, there are many centers who are just gearing up really with expertise in order to do some of these studies.

A brief mention about definitions. GERD is a term that's tossed around fairly loosely. I just want to differentiate between gastroesophageal reflux and gastroesophageal reflux disease, GERD, in other words, the presence of a complication. These complications include esophagitis; peptic stricture; Barrett's, which does occur in children, albeit with fairly low frequency; failure to thrive; pulmonary or ENT, ear, nose and throat disease, supraesophageal; Sandifer's Syndrome, or torticollis.

What are the management goals? I think we can agree, hopefully, that the common goals that we're testing are to relieve symptoms, to prevent complications, to heal esophagitis, to maintain remission, and to treat complications.

It's going to give my neck a break from this side.

Okay. A brief mention about prevalence and natural history. Suzanne Nelson has done a couple of terrific studies. This one, 1997, prevalence of symptoms of reflux during infancy, cross-sectional community, practice based, almost 1,000 healthy children below 13 months of age.

The infant GER questionnaire devised by Sue Orenstein has been shortened and revised. That only takes five minutes rather than the approximate 20 minutes that the original took. The main outcome measure is the reported frequency of vomiting.

In terms of her results, vomiting was found to occur at least once a day in half the children below three months; at least once a day in five percent at ten to 12 months; a peak frequency occurred at about four months of age; and there was a decrease from 61 percent to 21 percent between six to seven months of age.

You can see this very dramatic drop-off between these months. The peak frequency of vomiting was reported to be a problem by parents, 23 percent at six months and dropping off again further to 14 percent at seven months.

Now, I'm not going to quote all of Suzanne Nelson's studies or the others, but I'm just going to summarize them to say that the natural history of the disease is below two years of age, very often, almost always physiological, especially below the age of six months, 90 percent resolved within 12 to 18 months. These are -- I'm sorry I left the dates of here -- data from Carr and Nelson.

Above the age of two years to adulthood, first of all vomiting above the age of two years is never physiologic. GERD is usually a chronic relapsing disease in the over two year old child, as it is in adults.

The presentation, the age related presentations at around two to four years of age, similar symptoms and signs to younger children. Heartburn is very unusual, again, from one of Dr. Nelson's studies.

Above the age of eight to ten years, the signs and symptoms are similar. Presentation depends on the nature. The nature of vomiting may be effortless versus forceful or projectile. The disposition of the child, in other words, what we do with these children, and how we investigate them or not differs between the fat, happy spitters, those children who are thriving versus the unhappy, irritable child who may have poor weight gain, in other words, the child with a complication.

What about available treatments? Well, the different managements that are employed include explanation, reassurance, diet, life style, position, antacids, anticholinergics, botanicals gone out of vogue, prokinetics. Metoclopranide is not a good drug in children. Cisapride is not available to us. I forgot to mention erythromycin. H2 receptor antagonists, and then the old standbys of prayer, meditation, Vega therapy, and the cause of all ills, Candida treatment or Candida as a problem, rather.

But really what I'm going to focus on is the treatment of severe GE reflux disease, big league GE reflux disease, and for that we've got anti-reflux surgery, PPIs. I've put endoscopic treatment in parentheses because it's in its infancy, and hopefully it will not make it to children for several years.

Why is anti-reflux surgery important? Excluding minor procedures, like Inguinal herniorrhaphy, central line placement, in the United States anti-reflux surgery is the commonest operation performed by pediatric surgeons.

I should just mention that in the years 1993 until the year 2000 at our institution in Vancouver, British Columbia, with the judicious selection of patients and use of PPIs, we have cut our annual operation rate from 50 anti-reflux procedures per year to approximately five new anti-reflux procedures per year.

A brief word about etiologies underlying diseases and mechanisms, and I'm really just going on

focus on underlying disorders.

We know that the conditions predisposing to the worst GE reflux disease are as follows: neurologic impairment -- I won't go through all of the reasons for these, but I can certainly address these if there are questions -- neurologic impairment, a variety of reasons; repaired esophageal atresia. This is an esophagus that's never functioned properly in utero, even if surgical continuity is established. Chronic lung disease.

And then in children who don't have underlying systemic diseases, I believe that hiatal hernia is a very under recognized cause of GE reflux disease, certainly if one knows how to recognize it endoscopically, it is present in my experience in almost every patient with Barrett's esophagus and almost all patients with erosive esophagitis.

And then, of course, the mechanism of transient lower esophageal sphincter relaxation.

What about acid secretion? We're talking about using acid suppressing drugs, but what about acid secretion? Does it occur in children?

A couple of excellent studies that have been done. In healthy term infants, there is relative hypochlorhydria only for the first zero to five years of age, normalizing by about six to eight hours of age. The normal basal acid output of 25 plus or minus ten micromoles per kilo per hour approximates that in adults.

Hypergastronemia occurs despite normal acid secretion. A study by Art Euler, who I believe is in the audience, 1977.

Paul Hyman, in Gastroenterology in 1983, a colleague also at UCLA with me. Enteral feedings are necessary for normal oxyntic mucosal secretion. In the purely TPN fed child, these children are relatively hypochlorhydric.

Paul Hyman also showed in 1984 that meal stimulated secretion occurs, but it's weaker than in older infants, in other words, those above six months.

Again, Dr. Hyman showed this time in healthy pre-term infants that basal acid output by seven days of age was relatively low at 12 micromoles per kilo-power (phonetic), increasing over the first month of life to within the older child and adult ranges of about 30, again, micromoles per kilo-power.

And very few infants are, in fact, achlohydric, and it's pentagastrin-fast achlorhydria in the first week of life.

So, in summary, with regard to acid secretion, yes, pre-term and term infants do make acid. So these drugs are definitely relevant to us. Acid secretion increases rapidly to that within adult ranges on the basis of micro moles per kilo-power.

Pentagastrin responsiveness occurs by one to four weeks of age. The increase in secretion depends not on gestational age. Rather, it depends on postnatal age.

And infants require enteral feeds for normal acid output.

A brief word on pharmokinetics. I know we've got individuals in the audience and speakers who are much more expert than I at this. I'm just going to quote one of the studies I was involved in.

For omeprazole, and this was published by Tommy Anderson in our group who did the pediatric international omeprazole study, a study between six centers in Canada, some centers in Europe, Britain, and Australia, and our own international clinical study.

We know that the ontogeny of metabolism, the metabolic capacity, meaning these parameters, area under the curve, area under the curve normalized, the t-half, the Cmax, and the Cmax normalized, are highest between the ages of one and six years. We did not study any children under the age of one year in these studies; and that there is a gradual decline in metabolic capacity with increasing age to reach normal adult values by approximately 12 years.

And this accounts for the findings that much, much higher doses on a per kilo basis are required in the younger children than in older children and adults.

So if, for example, we extrapolate the dose ranges that we found in our studies, for example, approximately .7 to three milligrams per kilo per day in a 70 kilo adult, you can see what kinds of doses those would translate to.

And so the question is also if the PK characteristics are similar to the benzodiazapines, can we extrapolate to the under one year of age children.

And I think now to really the meat of my topic today, and that is looking at the endpoints, systems and signs and feasibility.

For the purposes of a study, in my view, the symptoms and signs should be definitely causally related to gastroesophageal reflux disease, most relevant to patient improvement, something we want to improve for the patient's benefit, prevalent, highly prevalent in the age group under study, measurable, hard, objective, safely accessible in the given age group, physically accessible in the given age group.

And by feasibility, I mean the ability to accrue an adequate number of patients in each age group to retain these patients in the study, and of course, these are integral to the success of the study.

So, again, this is my own little table drawn up just to see, and there may be other factors here, just my own view. This is not published at all.

I would propose the presenting symptoms and signs, the endpoints be subjected to at least some of these tests: vomiting, for example, frequency; heartburn and esophagitis.

Well, we know that vomiting is highly prevalent. We can measure its frequency. It's prevalent in all age groups.

Heartburn we know is only describable in certain age groups and certainly not in neurologically handicapped children. Esophagitis is definitely a hard endpoint in all age groups.

Then the question is: what about the degree of acid reflux, intraesophageal pH? Is that useful?

I've put a check mark and a question mark because although we can show that intraesophageal pH -- the degree of 24 hour acid exposure is decreased by agents. Does that relate directly to symptoms? In our own studies, we actually showed that it did in several mepiprazole studies.

And, in addition, there are some linsoprazole studies that I'm aware of using the same methodology.

Epigastric pain and irritability. Now we're getting onto slightly softer endpoints, much more subjective. Again, these may be the only parameters we have to use in such age groups, but we must acknowledge that these are softer.

What about failure to thrift? Actually weight gain is a good parameter in young children. It's not such a good parameter in older children necessarily, but of course, there are many other factors that go into it.

Then feeding problems, a very soft endpoint, very sort of catch-all phrase.

Respiratory problems, supraesophageal problems, dysphagia or odynophagia are very seldom complained about by children. Apnea, my own view is that apnea is not a good endpoint for children because it's -- and I'm sure we'll get more into this in discussion.

My own reading of the literature is that there's a very poor correlation between apnea and gastroesophageal reflux disease; also to mention that it's exceedingly difficult to study this particular parameter in infants.

And then, of course, are we interested in the degree of acid suppression, in other words, the intragastric pH changes? In my view we're not that interested, other than doing PD studies, but we're not that interested for the benefit of the particular patient. We're not aiming to make the achlorhydric. We're just aiming to decrease the amount of acid reflux into the esophagus.

So, in summary, my own proposed requirements for performance of a successful study in children are it depends on the availability of other equal or better treatments. This may impact our ability to offer placebo.

Is the question that we're asking worthwhile? Is the protocol simple? Are the tests reliable? Are the tests not overly invasive, given the child we're studying?

What about the parents? Of course, we need willing parents to enroll these children, and we need the docs to be willing to discuss enrollment with parents.

And finally, as I alluded to before, we need pediatric studies that are qualified to carry out the specific proposals.

So a couple of questions. Dr. Gallo-Torres has already addressed a couple of these, and I'll just ask them as questions.

Is the age group less than the dividing line, less than one year versus one to two years and up to 17 years; is this a sufficiently sensitive or adequate age group breakdown? Do we need others? And what should they be?

Are there indications for PPI use in all age groups? I think that's a basic question we do need to ask. Do we need PPIs under the age of a year?

Efficacy. Can we study it in all age groups? If not, can we impute efficacy from other studies? It may be very, very difficult to study efficacy in some age groups.

What are the appropriate study endpoints in each age group? And what are the dosages?

And of course safety in each age group.

Thank you very much.

CHAIRPERSON CHESNEY: Thank you, Dr. Hassall.

Our next speaker is Dr. Hudak, a member of the committee who's going to talk about clinical trial design related to studies of protein pump inhibitors in the neonate and the premature infant.

DR. HUDAK: Good morning. I've been tasked with a formidable number of assignments here to get done in 15 minutes, but I just want to review what those issues are.

And the primary task was to talk a little bit about the huge controversy that exists in our field with respect to any association between apnea and gastroesophageal reflux. Like many other things in our field, despite 20 years of intense study and debate and literature, this is still not clear.

I was also tasked with talking about what the current management of apnea associated, GR associated apnea is. Is there a standard across the country?

And the answer to that I think you'll see is no.

To talk a little bit about issues with respect to clinical trials in this very different population of premature infants and neonates less than one month of age.

And then finally, some specific issues with respect to potential trials of PPIs in this population, touching upon some of the clinically meaningful outcome measures and some of the other measures, short and long-term efficacy safety measures.

So just to review here, gastroesophageal reflux is, I think, when we talk about it, it means one of two things. One is regurgitation, and the other is sort of just reflux that's caused by relaxation of the lower esophageal sphincter, and depending upon whether you're a lumper or a splitter, you're talk about these things separately. I mean, they clearly have different sorts of mechanisms. They have different prognoses.

Having lost about four or five ties when my son was about three to five months old, I'm well aware of the regurgitation phenomenon. That's a very self-limited one.

The actual reflux itself that may not manifest with regurgitation is typically caused by relaxations of the lower esophageal sphincter.

Both of these things, regurgitation and reflux are considered to be really physiologic because they're both very, very common in premature babies and term infants. And if you look at the information that's been done in healthy term infants -- and there are articles in the handout that go through that -- the sort of incidence of reflux studied by pH probe or other means sort of peaks at about three to five months of age in terms of the number of episodes per day; in terms of the reflux index, which is the percent of time that the esophagus sees a pH less than four; and in terms of the maximal duration of an episode.

And then that sort of gradually abates, but never really clears. In fact, adults have -- for pH probe in normal adults, you'd have reflux there, which would be asymptomatic as well.

Now, in terms of risk factors for reflux, there are a number. Positioning and posture is very important. Pretty much everything we do in the nursery is to encourage reflux in the premature population, and there are good reasons for that.

We tend to attempt to restrain babies in a careful way. There's no JCHO representatives at this meeting. We don't use restraints. We use the word "snuggle" or "nest" infants in a developmentally appropriate configuration.


DR. HUDAK: And they're very happy with that, but that puts them in a prone position and sometimes with the left side down, and these are things that tend to work against gravity and tend to drain stomach contents up toward the LES. So those are issues.

Positioning, of course, is something that has been linked with SIDS, and this is exactly the sort of positions that increase the risk of SIDS, but we all have these babies on monitors. So we catch any potential problem quickly.

There are a number of things that will increase gastric pressure in babies, including how rapidly you feed babies or how rapidly babies sort of feed themselves; the intervals of the feedings; the type of formula that may be used, whether it's a breast milk or a higher osmolar type formula will make a difference.

There are abnormalities of the abdominal wall. For instance, the status post repair of gastroschisis, you sort of close the wall and there are forces that tend to increase gastric pressure.

Decreased lower esophageal sphincter tone, again, that is physiologic in premature babies. That tone increases over time, but at least in the early part it tends to be quite low. There are drugs that we use, such as xanthines, in babies that will decrease LES tone.

Abnormal esophagus you've heard about in terms of babies who have had repair of esophageal atresia, babies with hiatal hernia, other esophageal abnormalities.

Lots of reasons that basis who are premature will have neurological abnormalities, whether it's immaturity, dismaturity, or frank neurological abnormalities or injury.

Term babies, status post ECMO, have been described by at least one author as having an increased tendency for reflux.

And finally, there are a number of factors that can cause babies to have delayed gastric emptying, and this, of course, will tend to increase the tendency to have reflux.

In terms of the diagnosis of reflux, most of the time in the nursery what we do is rely upon our clinical observation. So if the baby sort of is in bed and sort of has an asymptomatic spit and necessitates a bed change, that causes a lot of attention.

Occasionally with babies who have feeding related bradycardia and so forth, we will study them most of the time with a barium swallow or upper GI series. We rarely do pH probes these days. They have sort of gone out of favor, at least in our area, although other institutions do use them.

There are manometric techniques that will look at pressure changes in the esophagus, and the newest technique that's been written about is this multiple interluminal impedance technique, which is much more sensitive than a pH probe because it will also detect nonacidic reflux into the esophagus. So you can actually see bolus of material, different levels of the esophagus, with this technique.

Now, the mechanisms, reported mechanisms that cause apnea in babies who may reflux, it's clear with healthy spitters, they have a mechanism that's very different than infants who may have apnea mediated by a laryngeal chemoreflex. And I tend to believe that both of these things happen. I think it has been well described in healthy spitters that the contraction of the diaphragmatic muscles and the abdominal respiratory muscles occurs at the same time that there is a reflex closure, anatomical closure of the larynx. So that's before any gastric contents make their way to the larynx that that happens, and that is followed by some pharyngeal swallowing and maybe by a short period of apnea in term babies, very brief, not invariable by any means, and then by coughing and sneezing to a variable degree.

Babies who actually have reflux and get formula or gastric contents in their larynx, it does stimulate a laryngeal chemoreflux leading to airway closure; apnea, which may be prolonged, lasting over ten to 20 seconds sometimes; pharyngeal swallowing; and attempts to clear the airway in that respect.

so I think that really does happen, and that's been pretty well documented.

The question of whether or not esophageal reflux, that is, material makes it way somewhere in the esophagus, but not in the pharynx and not into the larynx, whether that is associated with apnea, whether it's an acidic reflux or nonacidic reflux, in my mind, looking at the literature, that can't be said with certainty one way or the other.

Now, this is a very voluminous literature. You only have a very small amount of literature in the packet. There are hundreds of articles literally over the years looking at different populations with different techniques, making different statistical analyses, using different measurements.

And basically I sort of like to summarize my understanding, and this is all debatable, but my understanding of this literature is that apnea and reflux both occur commonly in pre-term babies. They co-associate. It is very much -- that doesn't mean they are causally related one to the other. It's very much like the old studies of necrotizing enterocolitis in babies where things like umbilical artery catheters were associated, but, in fact, NEC occurs in tiny babies who are very sick, who have UACs or have had UACs back then, and on careful examination of all that information, the UACs were not found to be a risk factor for NEC.

Similar to the association of IVH and RDS in pre-term babies, a very immature, very vulnerable population, co-morbidities, co-associate.

Now, the older studies that first described the association of apnea with reflux really failed to look at it carefully in terms of the temporal relationship. That is, they found a lot of reflux in babies who have lots of apnea, but they couldn't relate one event to the other.

The more recent studies -- and I think there are three or four in the packet -- looking at the universe of premature infants, that is, infants with apnea and so forth, have really been unable to establish in the broad population any statistically significant correlation temporally between acid reflux, non-acid reflux, and apnea. And it's looking at it with pH probes, with multiple impedance techniques, or looking at just clinical regurgitation in babies, nursing observations, and so forth.

However, I think it's pretty clear that at least in selected subjects, that there is a population of babies who got fairly significant symptoms, who have apnea by definition since they're being treated with xanthines, that is resistant to xanthines, who do respond to positioning, thickening of feedings, and surgical anti-reflux procedures with a tremendous diminution of apnea.

And how that sort of happens is not really clear as a mechanistic point of view, but that's an important population to identify because I think those are the patients who may demonstrate some benefit to medical anti-reflux therapy.

Now, what is the current practice for treating reflux? Well, positional therapy, postural therapy is universal. Everybody does that.

A variety of feeding manipulations. Again, I think the key here is babies who spit up have residuals, have apnea. They go on to continuous feedings where the feedings are put on a pump and given over one to three hours. So it decreases the amount of volume introduced into the stomach per unit time, decreases gastric distension and pressure, and the feeling is that that does in some babies tend to minimize apnea and reflux.

Decreased osmolarity, that commonly happens. Thickening of formula is very variable, very variable across the country. Some people think with thickening with rice cereal actually, even though you get some symptomatic relief, may make the esophageal reflux worse.

Medical therapy. Neonatologists are trigger happy with drugs. One of my major tasks when I come on service is to try to decrease the drugs from at least 15 down to, you know, ten or some manageable amount in the pre-term baby, but commonly babies are put on a variety of acid blockers. Ranitidine is the one that we use now.

Cisapride, before it was taken off the formulary basically for complications and for lack of efficacy, was very common. There's data in the packet that says that, you know, 70, 80 percent of babies were discharged on cisapride. We used to call it Vitamin C. Anybody who had a residual would go on cisapride. It's unbelievable.

And right now reglin (phonetic) had sort of gone out of favor when cisapride came in, and now there's a trend back, I think, across the country, taking an informal survey, to more use of metoclopramide for treatment of residuals, apnea, possible reflux.

Now, specific considerations in pre-term infants. This is an extremely vulnerable population of babies. We have to really focus a lot on the risk-benefit considerations for any particular study. Treatment of one group of symptoms may cause side effects and adverse issues in another organ system.

We at least want to see that there's some rational physiologic basis to treatment so that is, you know -- with the PPI, if the rationale is it decreases acid production, the hypothesis would be that that by itself would decrease some of the perhaps vego-vagal reflex mechanism of apnea, and so forth, that we haven't proved exists, or it may change the distal esophagus so that it's much more protective against reflux. Those are very speculative sorts of things.

A lot of the reflux in babies is nonacidic because they get fed often and it's buffered. So making up a rational physiologic basis for PPI therapy in pre-term babies is a little bit iffy.

And then long-term follow-up is obviously very important. And one of the questions is what appropriate age for long-term follow-up, and in my bias it's somewhere between one to two years.

There are multiple co-morbidities and confounders in babies that we have to recognize. It's difficult doing studies in pre- to term babies because we can't ask them if they're having more heartburn. They sort of don't tend to respond to those sorts of questions.

It's important to conduct the studies have equipoise, and that's something that's often missing. There's some therapeutic skepticism about the intervention that you're using.

Knowing the natural history of the disease is important in terms of timing the therapy. So if you've got a condition that developmentally fades out, you can deceive yourself into thinking the treatment is effective if you don't have controls.

Meaningful clinical endpoints are sometimes very difficult to come up with. I think in this case we'll talk a little bit about what those are in this population.

And then finally, the selection of the population is critical. If you enrolled everybody with apnea or obstructive apnea, I think you're not likely to find an effect. I think you have to identify patients who got lots of apnea, unresponsive to conventional therapy, and who also have demonstrated reflux, whether it's acidic or non-acidic by one of those measures of analyzing it.

So just to give you one example of this issue with populations, and this is perhaps stating the obvious, but sometimes it's useful. We went through about 15 years ago lots of studies on serfactin and pre-term infants, and the primary endpoint there was intact cardiorespiratory survival, that is, that the hypothesis was the surfactant would improve the incidence of baby surviving without chronic lung disease.

Everyone thought that if the surfactant diminished the acute respiratory disease, the babies would clearly have less chronic lung disease. But we found out the hard way that that was wrong, that the chronic lung disease by and large is a developmental phenomenon that is minimally influenced by early lung disease.

The risk factors, I think, from chronic lung disease are gestational age. Suppose for a minute that air leak babies is another risk factor that' important. We know that serfactin decreases air leak substantially. You can prove that it decreases from 20 percent to ten percent with a population size of 400.

All right. If you chronic lung disease among kids with air leak is 75 percent instead of 50 percent, and your reduction in air leak from 20 percent to ten percent reduces that risk to 50 percent, then your chronic lung disease -- this is a typo -- actually in that population goes down from 55 to 50 percent in the whole population, taking all comers, and to identify that with statistical certainty, you need thousands of babies to study.

All right. The population that would be amenable or would respond to the surfactant in terms of decrease in chronic lung disease is a small portion of the overall population of premature babies. So you need lots and lots of babies to study.

Now, neonatology, again, just to sort of state some history. We're intense with this. We into instant gratification. We like to get on the bandwagon. If there's a new treatment out there we use it. Usually there's no investigation or little investigation, no due process.

It may get to be a standard practice, as has happened with metoclopramide, as happened with cisapride, without there being any evidence of efficacy and with, in fact, in some of these circumstances there being significant safety issues that arose later.

And then finally some cooler heads prevail and go back and do the studies that show is there or is there not efficacy or safety.

And I can put up the list here of things that have been studied, I think, relatively poorly, where we've sort of learned again and again from the history that therapies are not benign, and most recently with the steroid phenomenon, we've gone from using steroids in 80 percent of babies less than 1,000 grams to very, very infrequently because of the neurodevelopmental follow-up data that has come out on that population that suggests that those babies have increased cerebral palsy and other significant neurological problems.

And, of course, this sort of applies to intensivists of all sorts, but it's good to keep in mind.

Now, for PPIs, just a few points. I think reading the literature there is no evidence that gastroesophageal reflux in pre-term babies, in healthy pre-term babies, that is, babies who don't have accompanying chronic lung disease, neurological problems, and so forth, all right, is any different in its outcome than the same reflux in healthy term babies. So the question is: why would you even want to treat it?

There is no evidence that acid gastroesophageal reflux produces more frequent or more severe either esophageal or super esophageal symptoms than non acidic reflux. The studies haven't been done. No one has looked at that sort of simultaneously.

And there is very little evidence that some of the anti-reflux medications that we use now, ranitidine and metoclopramide, really affect any of the super esophageal symptoms in pre-term babies. Very little evidence, indeed.

And so when we look at these trials in pre-term infants, I think selecting clinically relevant efficacy endpoints is important. I mean, I would suggest sometimes the simpler the better in these things.

I think at the bedside, anyway, our primary issues are significant apneas, bradycardias, and desaturations, and the types of interventions they need from the nursing staff. So a baby who needs to be bagged vigorously, that's a significant complication.

Documenting reflux or reflux episodes by pH probe in an asymptomatic baby is not a very significant endpoint.

On the other hand, I think it's important if you study these agents, you need to look at reflux to start with and reflux to end with and see if you have any effect and see if you have any change of symptoms.

Secondary endpoints in these kids, clearly less hospital stay would be an issue because a lot of these kids stay in the hospital for prolonged apnea. Whether this might affect the use of home monitors, and whether it might alter their profile of discharge medications, other agents that they might not have to have if they're on a successful anti-reflux medication.

In terms of safety, the things are growth. Infection is an important one because suppression of gastric acid may have some ramifications in terms of gastrointestinal flora, intestinal infections, and whatnot.

Feeding tolerance, liver function with the PPIs in pre-term infants is probably important to look at.

Various drug interactions with other prokinetic agents, and so forth, and a two-year neurodevelopment outcome.

Careful selection of the study population I alluded to is critical, and then, of course, the study decision. I think Dr. Wilfond is going to talk about that some, but I think what's proposed in the WR is a randomized withdrawal study, and I would be interested in hearing everybody's thoughts about that study versus traditional placebo controlled, which in my mind has a number of positive points associated with it.

So I think I'll end there. Thank you.

CHAIRPERSON CHESNEY: Thank you very much, Dr. Hudak. It clarified a number of issues for me.

Our next speak is Dr. Wilfond, who's going to discuss the ethical issues of using randomized placebo controlled withdrawal trial design in pediatrics. And I understand he has a Macintosh presentation that may take a few minutes to set up. Is that still correct?

While we're waiting, although --

MR. WILFOND: Where's the microphone.

While the slides are going on, I can actually begin my talk just to sort of move us along.


MR. WILFOND: I'll just probably step over a moment to adjust something as the time comes up.

It's a pleasure to be here. One of the things that I was struck by listening to the last talk was the realization that as a pulmonologist who takes care of these children after they go home from the nursery, that reflux meds. are the least of our problems.

We also have enormous confusion on how to use the monitors themselves, and even worse than the reflux meds. is the use of diuretics, which an abysmal sense of confusion. So I really applaud this group for tackling this issue because I think it is a very important issue.

The first slide that I'll show you in a moment will describe the six major issues that IRBs are tasked to look at when they consider research, and what I'm going to do today during my talk is to try to take the issue of placebo controlled trials and try to refine it down to what I consider to be the essential concern or the essential issue based upon walking you through the regulations and how the regulations apply to pediatric trials.

It look like I'm about to come on. I guess not. But anyway, the == I keep on thinking it's about to happen, and then it's getting slow.

Essentially the general regulations for research include six main criteria, and the first three criteria have to do with the balancing of risk and benefits, and clearly, that's where the issues of placebos come around, trying to not expose children to unnecessary risks and to maximize safety.

Okay. There you go. I think I can talk pretty loudly.

So this was the slide I meant to show you before. Just the first three regarded the issues of safety and benefits.

But for the pediatric regulations though, we have a little more of a complicated design, but where's the little pointer?

And so for pediatric regulations, we tend to actually ask a series of questions to try and decide how to assess the research, and the first question has to do with whether there's a prospect of direct benefit or no prospect of direct benefit.

And in addition to that categorization, we have to decide how much risk there is and the categorizations of risk are minimal risk, a minor increase over minimal risk, or a greater than moderate increased risk over minimal risk. You can see these are sort of hard to be clear exactly what they mean with that alone.

But the importance of this categorization is that based upon which category it is, there are additional considerations to address. So if there is a prospect of direct benefit, then we have to ask the question about whether the risks are justified by the benefits, and whether or not that ratio is as favorable as the alternatives.

However, if there's no prospect of direct benefit, then we have to look at whether the risks represent commensurate experience and whether it provides vital knowledge about the subject's disorder.

And certainly I think this is an area where there's no question that I think this is a very important issue.

So the first question that we have to decide if we want to consider how to look at a placebo controlled trial, such as the ones we're considering here, is how to categorize that trial within those regulations.

And the first challenge is whether we apply those risk categories to the entire study or to the individual component. So do we ask the question: should this entire trial be no prospect of direct benefit or do we look at specific components?

And by specific components, I mean, you know, if we're doing pH probes, proton pump inhibitors, the placebo, the blood draws, do we look at each of these as a group or do we look at them separately?

And the problem of looking at them as a group, is that then the benefits of one could justify the risks of the other. So we thought, for example, that there was great benefit to looking at PPIs. In theory one could then justify doing liver biopsies on children.

And so, you know, I think intuitively we have a sense that that perhaps is not the way we ought to be doing things. It's perhaps better to look at things as individual components.

So the question we have to then ask is: how should the placebo arm itself be considered?

And before I get into that analysis, I want to give you some what I would describe as intuitions about placebos. I think we all have a sense that placebos are not acceptable, particularly if there's an effective intervention to avoid significant morbidity and mortality.

So, you know, we wouldn't use placebo controlled trials for leukemia, for meningitis, for status epilepticus, for status asthmaticus. These are serious enough diseases for which there are interventions, although not always effective, that we would not consider putting a person on a placebo and not active treatment.

However, there are many groups that have looked at the question of placebos and tried to identify when are placebos appropriate, and the examples I'm going to give are fairly familiar. These are from the American Academy of Pediatrics, '95, Committee on Drugs, and they suggest that when there's no commonly accepted therapy, if the commonly used therapies has questionable efficacy, if the commonly used therapy has significant side effects, the disease has spontaneous exacerbations or remissions, or the placebo is an add-on to established therapies. So these are the general types of reasons that we think the placebos are acceptable.

So what I want to do is to try to take these reasons and try to place them within the regulations as it relates to our trial. So in order to look at the risks and benefits of the placebo arm, we have to clarify what would happen without the trial, and that's necessary to assess the relative risks and benefits because we have to assess them compared to some baseline.

And so the first question we have to ask in terms of that baseline is whether or not the placebo arm offers a prospect of direct benefit compared to that standard alternative, and if that's the case, then we would look at it under the regulations of 405.

However, if we think it does not offer a prospect of direct benefit, then we have to consider whether or not the placebo arm poses more than minimal risk or is more than a minor increase over minimal risk.

If it was more than a minor increase, then the approval process would be much more complicated. So I'm going to make an assumption that when we look at this trial we're going to be looking at it either under 405 or 406.

So I think the main issue though is summarized by the last speaker, is that, you know, the standard treatment is to use a range of anti-reflux meds., but as was described, that the efficacy and the value of these is uncertain, although the good news is that the risk of these drugs that are currently on the market is relatively modest.

However, I think it would be hard to make the claim, at least in my view, that putting people on placebos offers them a prospect of direct benefit compared to what they otherwise would be getting with treatment.

So the question we have to ask is whether the risks of the placebo arm are more than a minor increase over minimal risk.

Now, I think what's rally key here, and I'm going to go through the two studies briefly, is that the Study No. 2 is taking people who are being monitored and where there are interventions available for apnea. So to the extent that our endpoint is apnea, these are people who are in a very carefully monitored setting.

So, you know, putting somebody on placebo in that setting, I think, would have less risk than if they were in an unmonitored setting.

And, again, I think it was discussed before, the whole approach of withdrawal of patients who are having concerning symptoms provides another safety way of trying to minimize the harms.

In the Study No. 4, which were the infants from one to four -- 11 months of age, rather, they exclude children with ALTs, which I think is probably a good thing because those are the patients who would have had the most to lose by being placed on a placebo.

However, it's complicated, and I have to admit this is where I'm a little in my own mind unclear what to do for two reasons. One is that those are precisely the sorts of kids that we are most interested in treating.

But an additional challenge though is how do we define an ALTE because, again, seeing this in the hospital, you know, many parents will say, "My child stopped breathing."

And you ask them for how long, and they will say an hour. And you know that's not really what happened, and you have to really sort of walk back and try to sort out what was going on.

So I think the issue of out-patient ALTEs and how they're categorized and how people are excluded on that basis.

So ultimately, the question about whether the risk of being a placebo arm under these conditions is more than a minor increase under minimal risk I think can boil back up to the three questions.

One is whether there's any unnecessary risk that can be further identified, whether that risk can be minimized, and whether having a DMC as has been suggested in the written request will help that also.

So I think that in the end whether it's no more than a minor increase is based upon a judgment that what we expect will happen in children in the placebo group.

And I think as long as under the described conditions, and clearly, they need to be articulated with a little more. So I'm really talking more on general principles, but I think under the described conditions particularly in terms of people being monitored, excluding ALTs, having a withdrawal program, that reflux in both groups would not be expected to cause significant harm to the children in comparison to children in the active treatment groups.

And I think because of that, I think the placebo arm does not pose a greater than minor increase over minimum risk to these children. So this is my quick reading of this, and I'll be interested to hear what people have to say, but I think the main point I want to make is that I don't think that placebo controlled trials in this population are necessarily ethically problematic as long as they're done appropriately.

I'm done.

CHAIRPERSON CHESNEY: Thank you very much, Dr. Wilfond.

We were scheduled for an open public hearing at 9:15. So I think we need to ask if there is anybody that wants to speak to this issue.

DR. PEREZ: We have two open public hearing people. First I'd like to recognize Dr. Gardener.

DR. GARDENER: Good morning. My name is Jerry Gardener, and I'm with Science for Organizations, a scientific consulting company that works with pharmaceutical and biotechnology companies, and I'm here representing Science for Organizations.

The main point I'd like to make is to suggest to the committee that they consider emphasizing the effect of proton pump inhibitor on gastric and esophageal pH instead of emphasizing the pharmacokinetic measurements.

This slide summarizes my background and experience. I served as Chief of the Digestive Disease Branch of the National Institutes of Health and held the IND for omeprazole when it first became available.

If you could, go back one.

I held the IND for omeprazole when it first became available for human use. I've designed, conducted, and analyzed results from studies with a number of proton pump inhibitors, as well as histamine H2 receptor antagonists, and I've analyzed data from over 1,000 gastric and esophageal pH recordings.

Next slide.

This slide summarizes the reasons that I'm suggesting that you emphasize the effect of proton pump inhibitors on gastric and esophageal pH instead of the pharmacokinetics of proton pump inhibitors.

First, there's no correlation between pharmacokinetic parameters and effects of the drug on gastric or esophageal pH.

Second, the effect of the drug on gastric and esophageal pH reflects the action that leads to clinical efficacy.

And, third, measuring the effect of proton pump inhibitors on esophageal pH in GERD patients can confirm the diagnosis.

And finally, I think that pharmacokinetics should be assessed, but only in a limited way.

This slide illustrates typical results from pharmacokinetic measurements and pH recordings with a proton pump inhibitor. The data given in the left panel are medians from 26 healthy adult subjects, and in the middle and right panels are from 19 adult subjects with GERD.

The left panel shows the plasma concentration time curve for a proton pump inhibitor given just before breakfast, and as you can see, the plasma concentration peaks at approximately four hours, and then decreases, and there's no detectable drug in the circulation after ten hours.

The middle panel shows gastric acid concentration at each hour during a 24-hour recording period. The curve in blue was obtained at baseline, and the phasic decrease in acid concentration is caused by the ingestion of meals which buffer gastric acid, and then this is followed by stimulation of acid secretion and a subsequent rise in gastric acid concentration.

The curve in prink was obtained after a single dose of a proton pump inhibitor just before breakfast. Three to four hours after dosing, there's a significant decrease in gastric acid, and this decrease persists for at least 24 hours. Thus, even though there's no detectable proton pump inhibitor in the circulation after ten hours, there's a persistent effect of the drug on gastric acid.

The right panel shows the esophageal acid concentration measured at the same time and then in the same patients as gastric acid in the middle panel.

The curve in blue was obtained at baseline, and the increase in esophageal acid concentration results from reflux of gastric acid into the esophagus during the post prandial period.

The curve in pink was obtained with a single dose of a proton pump inhibitor given just before breakfast, and you can see that the drug virtually abolished esophageal reflux in these patients.

So, in conclusion, this slide illustrates that there's no correlation between the time course of action of a proton pump inhibitor and its pharmacokinetic time course.

Other analyses that I won't present show that there's no consistent correlation between any pharmacokinetic parameter and any measure of the effect of the drug on gastric or esophageal pH.

Thank you.

CHAIRPERSON CHESNEY: Thank you very much, Dr. Gardener, for clarifying that very important issue.

Our next speaker at the open public hearing i is Dr. Kerns from formerly the University of Arkansas. I'll let you introduce yourself now.

DR. KERNS: Thank you. I'm Greg Kerns. I'm Chief of Clinical Pharmacology at the Children's Mercy Hospital in Kansas City, Missouri, and Professor of Pediatrics and Pharmacology at the University of Missouri at Kansas City.

My comments admittedly are somewhat spontaneous, hopefully will be considered, and I first want to declare publicly that I have been a consultant and an investigator for many companies that study acid modifying drugs in children, which includes Merck, Reliant Pharmaceuticals, Wyeth Ayerst, Santarus, and pretty much if they made one, I probably talked to them.

I also need to disclose publicly that I am also a consultant to the Food and Drug Administration. So if anybody is totally conflicted, I guess that would be me.

I want commend the Advisory Committee for having this hearing, and particularly with respect to taking on this topic. I think we've all heard this morning a variety of things from how to do it, how not to do it, how should we do it, how much we do it, and perhaps just recently, perhaps we shouldn't do anything, as was mentioned.

I don't know that my view is the same. I think I can break my comments down into three areas: what we must do, what we should do, and then issues about what we can do.

First, what we must do. From the '94 pediatric rule through the '98 rule to the Best Pharmaceuticals for Children's Act, everyone agrees that what we must do is to make information that will let use drugs in children better.

It's like the recent alignment of the planets if you've watched things in the evening where you have a wonderful -- for those astronomers like Ben Gold. Rarely do we have such concurrence about what we must do. The will of the Congress is clear, and the will of the agency is clear, and the will of the investigators.

Then the issue of what we should do to me really represents an incredible conundrum, and I pick that word intentionally, because there is not agreement with regard to this particular therapeutic category and many others what we should do.

I think there are some things we can follow. We should do things that are responsive to the needs of the patients and responsive to the needs of their families and responsive to the needs of the physicians and the other health care professionals that are charged with providing day in and day out care to these children.

Therapy has to be linked with knowledge, and hopefully that knowledge will give us guidance on how to use, when to use, and when not to use.

And some of the success stories that have been part of the pediatric initiative are clear with the implications on labeling of some drugs that we have actually learned we probably shouldn't use.

Other than being responsive, we have to be responsible in what we do. There are issues, ethical issues, that are very concerning, and I'm speaking now as an investigator concerning as we present these studies to parents and children to solicit their participation.

I would argue that as a partner and as an advocate for children, convincing someone to be part of an admittedly underpowered study to assess efficacy, but rather to ask questions about clinical utility poses little advantage, little incentive to subject the child or their family to the rigors of an investigation where the answers may well be known.

It's critical that we be responsible in using the information that we have. It seems that every day we wake up and look at a new proposal to study a new compound. It's like deja vu al over again. And I wonder many times is it really necessary.

Do we utilize the information that we learn in the next study as opposed to creating a grand crescendo that makes each and every study more onerous, more difficult, and unnecessarily more risky than the one before. We have to take care and caution with that.

And lastly, what we should do, it's clear that we have to do things that are reasonable, and Dr. Hassall made excellent points in his discussion about doing things that are reasonable and realistic and will answer the questions.

The last thing I wanted to comment on is the issue of what we can do. We're in a wonderful time in pediatric clinical pharmacology where we have tools at our disposal that many of us spent years developing, and more years dreaming about.

Dr. Spielberg has on many occasions talked about the importance of understanding the association between the ontogeny of drug metabolism and physiology and linking that together to make responsible studies and study designs.

I think we have to heed that prudent advice and even turn it into a warning so that as we make study designs of drugs like this, we're not forgetting the things that are there for us. The fruit doesn't always have to hang at the top of the tree, and because of the expense and energy, we have to be wise in making sure that the harvest targets the intended population.

What we can't do is engage into some process of documenting clinical utility in the hopes that we'll answer perhaps an interesting question. At the end of the day children and their parents and their doctors are only going to be served by the kind of rigorous inquiry that answers to questions that are critical to making treatment decisions. That is not the abrogate the responsibility of regulators.

We have the best system in the world in the United States, but by putting things together, we can do it right.

And lastly, let me mention one thing that I hope the committee will consider. On April 1st, a draft guidance was published by FDA on exposure response relationships. If you've not read that guidance, I would argue all of you to read it.

This guidance is truly -- and I don't say this with any lack of sincerity -- a masterful work because it deals with the problem of identifying a target population and putting together the kinds of information that we just heard from Dr. Gardener to demonstrate that a drug has an effect that is or isn't related to its plasma concentrations.

And if that effect transcends all of the age groups, it's easy to define the dose, which at the end of the day every pediatrician, as they contemplate the drug, and we heard about the list of ten or 15 in neonatology, what's the neonatologist's first question? What's the dose?

So I hope you would consider that. I thank you for the opportunity to make these comments.

CHAIRPERSON CHESNEY: Thanks you, Dr. Kerns.

We'll try to remember the four Rs, responsive, responsible, reasonable, and realistic.

Are there any other speakers for the open public hearing?

(No response.)

CHAIRPERSON CHESNEY: Then what I would like to do if it's all right with our FDA folks is to take ten or 15 minutes to ask the committee and our invited consultants if they have questions of this morning's speakers.

No specific questions. So we'll take a -- I'm sorry. Dr. Fink.

DR. FINK: This is, I guess, a question for Dr. Wilfond.

In terms of a withdrawal trial, it would seem like a withdrawal study, although clearly ethical and feasible, would hide safety data. And has anyone designed a withdrawal trial where there is a control arm of non-diseased infants?

Particularly with proton pump inhibitors, I guess my concern is taking away the acidic barrier to gastrointestinal infection. If you start with the trial design that puts all infants on the drug, how are you going to see if it causes adverse side effects?

DR. WILFOND: Well, as I understand, and I may have this incorrect, too, because it is a little confusing, I understand this withdrawal design means there's a run-in phase where they're on the drug, but then they're randomized to either the drug or placebo, and then based upon certain predefined criteria, they're withdrawn from the study.

I'm asking this to the other speakers because Gil Gray was asking me this question before, and I think we may be confused about what exactly the trial design is.

Is my description correct?


DR. WILFOND: Then if that's correct, then, again, it's actually very similar to many asthma trials where there's an initial period on the drug, but then half are taken off. So you would be able to tell during that period of time whether there were any specific safety issues. Does that --

DR. FINK: Yeah, well, I don't know if that haws ever been applied like with asthma, where we're looking specifically at safety. Usually the safety trials are done first, and then you do a therapeutic or efficacy trial.

And I think it would mask safety if you run all infants in on the drug for a period of time.


DR. NELSON: I'd be interested in being corrected, but my understanding is that most of the safety data is generated by the description of the frequency of events within the population on the drug, and that at least the placebo designed trials are not powered relative to safety considerations.

So that it's unclear to me that you would need a placebo arm for that purpose.

DR. BIRENBAUM: I just want to clarify the placebo controlled, randomized withdrawal trial design so that everyone is on the same page about it.

In fact, this trial design has bene utilized multiple times in the past for the agency with asthma specifically as the condition being studied, and it was used because it was determined that there's a need for a placebo controlled arm, but exposing patients for prolonged periods, like three months, to placebo with a condition like asthma would be unacceptable.

So in such cases, all patients who are enrolled, eligible for enrollment into the study, are enrolled, and receive the treatment of study, the study drug; for a period of time that is determined would establish serum levels that would be correlated to some treatment effect, and after that time, if they continue to meet certain criteria, are then randomly assigned to either continued study treatment or placebo, and that is the period of drug assessment for both efficacy and safety, and it is usually of duration which the population is considered to demonstrate a long enough period of time for efficacy for which the study is powered and will hopefully unmask strong signals or any signals of safety.

But clearly, no study could ever be powered to safety assessments in the short term. They're powered to efficacy assessments.

This trial or any randomized withdrawal trial which has a placebo arm is no different in its duration of randomized withdrawal for the placebo arm than it would have in a standard, simple, placebo controlled arm in which you have no run-in phase. It would be a trial of the same duration.

The one disadvantage of this trial design is that at the end of the day in terms of long-term follow-up, no patient in this study will have received no study drug treatment. So at the end of the day, all patients who are looked at from the long-term follow-up assessment will have received study drug.


DR. FINK: Then I guess my question specifically with that design is for safety issues, why don't you also include a control group that is a non-disease, particularly in premature infants or neonates, a control group that is similar gestational age without GERD to look for -- to enhance your ability to detect safety signals.

DR. BIRENBAUM: It's an interesting point. However, confounders of that other arm may include whatever else might be the characteristics of that nontreated arm. So it might not be any different than looking at a historical control, except that the concurrent time period might be helpful.

But, yeah, that might be something to consider.

CHAIRPERSON CHESNEY: Are there any questions specifically directed for the speakers? Dr. Blackmon.

DR. BLACKMON: I wanted to clarify something with Dr. Wilfond because as I listened, it seemed to me the implication was that the active treatment arm didn't carry a risk, that your concern was with risks associated with placebo, and I'd just like you to speak to that.

DR. WILFOND: That's not what I meant. So I'm glad you clarified that. What I meant was by focusing on the placebo arm, I was trying to suggest that for the placebo arm where there was no specific prospect of benefit for those individuals, that then the issues would be how great is the risk.

For the treatment arm, where there is a prospect of direct benefit, then it's an issue of just balancing the benefits with the risks. But I wasn't trying to address that question. I was really focusing more on the placebo group.

DR. BLACKMON: But, again, that implies that the only potential benefit is with the treatment, and if you truly have not committed that this treatment is the treatment of choice, then how can you infer that that's the only group that gets a chance at benefit?

DR. WILFOND: I think what you're getting at is that risk and benefits are two sides of the same coin, and you can describe benefits as negative risks or risks with a negative benefit.

And so you're right. It gets very complicated in terms of how you want to look at it, and I think you could look at it either way. But from the point of view of one way of trying to interpret the regulations is to say that, you know, the alternative to these kids also is not being in the trial. Then they can do -- being in the placebo group itself doesn't offer them a benefit compared to if, for example, the parents wanted to not be in the trial and also not be on the drug. they could do that also.

So it's not clear that there's a specific benefit to be in the trial itself for that group.

DR. WARD: But if there is any adverse effect associated with the medication, the absence of that adverse effect it seems to me a benefit.

DR. WILFOND: I don't disagree with that. Again, it really is that issue of how do you choose to look at and define it, and I think that, one, I guess what I would say in spite of the analysis I presented, I also do think it would be feasible to -- actually in the few times I've tried this, regardless of which category of the regulations you use, you come out with the same answer. So it's not clear to me that you actually come up with different intuitions about what the appropriate decision is.

DR. BLACKMON: And the last point I'd like to make is that the discussion really hasn't dealt with the fact that there are non-medication interventions that Dr. Hassall covered for us that aren't addressed in the protocol. So that the placebo arm does get the benefit of what we do know about other mechanisms for controlling reflux.

DR. WILFOND: Can I respond real quickly?

CHAIRPERSON CHESNEY: Is that a specific question for Dr. Wilfond?

DR. BIRENBAUM: I guess it's a general comment. In looking at the design and the discussions about the design, we haven't really addressed the non-medication component of management.


Are there any other questions specifically for the speakers? And then we'll take a break. We've got many, many things to talk about.

Dr. Spielberg, you've had your hand up for a while.

DR. SPIELBERG: One more question with respect to randomized withdrawal. I think Dr. Birenbaum very nicely summarized the benefits of doing this kind of design from a safety point of view.

There's also a potential benefit from an efficacy point of view, Bob Temple's in Richmond idea where you look for patients, particularly for difficult to evaluate conditions, and I would posit the GI disease is probably among the most difficult to evaluate the outcomes, where you have a run-in period on drug. You take patients who appear to respond.

You then randomize to withdrawal, placebo versus drug, to see if, in fact, that response truly is attributable to drug, with a relatively short period of time to maximize safety for the patient. So there is potential benefit.

The question I have though is for randomized withdrawal designs, which I really like, it presupposes a degree of stability of process over time, and one of the things we're looking at here is a very fluid population where maturation of all the processes that we're concerned about is going on very rapidly, but very differently among different kinds.

And so I do have some concern about this kind of design in a situation where you have that much variability because the Ns then go up dramatically to actually be able to demonstrate effect.

CHAIRPERSON CHESNEY: One more questions and then our break.

Dr. Gorman, you have your hand up earlier.

DR. GORMAN: This is a question for Dr. Hassall.

You mentioned a dramatic decrease in the amount of GI surgery with a specific regime, but I'm not sure I got the details of the regime, you know, that you were treating GE reflux disease in a way that decreased the number of interventions. Did that or did that not include the agents we are discussing today?

DR. HASSALL: Yeah, there are two aspects to that that I didn't go into, and I appreciate the question.

Basically there are two ways that we approach it. First of all, we work very closely with the surgeons, the gastroenterologists and the surgeons, and we have much more stringent criteria for selection of patients for surgery than we did in the past.

So I might send the patient to a surgeon for surgery. The surgeon might come back to me with questions, "Did you do this? Did you do that?" which is not something that happens in a lot of institutions.

The second aspect is yes, and the main point that you are bringing out is that, yes, since I started using PBIs in children about 1989, 1990, around then, and we published the first study in 1993 on a group of 15 children who were refractory to all other measures. Their parents wouldn't let us take them off drug so dramatic was their response.

Since then we've learned how PPIs can be used judiciously, how in some cases reflux may be transient, may be delayed gastric emptying from post viral infection or whatever, but we make patients early surgery or long-term PPIs.

We withdraw PPIs. We see if they relapse. We withdraw PPIs later, et cetera, et cetera.

So it's a combination basically of better selection for patients -- of patients for surgery or PPIs and the use of PPIs in adequate dosage itself.


We're scheduled for a 15 minute break, and plan to be back here at 25 after ten. Is my watch correct?

So we'll start again at 25 minutes after ten with the questions and discussion.

(Whereupon, the foregoing matter went off the record at 10:11 a.m. and went back on the record at 10:27 a.m.)

CHAIRPERSON CHESNEY: We are ready to begin the discussion, and I'd like to turn the microphone over to Dr. Victor Raczkowski, who is going to present the questions to us and also maybe provide feedback to us as to whether we can make up our half hour.

DR. RACZKOWSKI: Hello. I'm Dr. Victor Raczkowski. I'm the Acting Director of the Division of Gastrointestinal and Coagulation Drug Products.

And to answer the second question first, in order to allow more time for discussion, I've discussed it with Dr. Murphy and the pediatric team, and we hope to extend this morning's discussion for at least an hour to have adequate time to discuss the proton pump inhibitor template.

And let me turn now to the questions. We have five questions for the committee, and the first question is: can the efficacy of a proton pump inhibitor for the treatment of pediatric patients less than one year of age be extrapolated from adults? Why or why not?

And as you've heard from our speakers this morning, the pediatric proton pump inhibitor template has taken the position that efficacy cannot be extrapolated from adults to pediatric patients of less than a year of age.

Question number two gets into some of the design issues of the studies, and are the designs of the efficacy studies requested for pediatric patients less than one year of age, that is, randomized, double blind, placebo controlled studies of a treatment withdrawal design acceptable? And if not, please specify the components of the study designs that should be changed, and please suggest an alternate ethically acceptable trial design to establish efficacy and safety.

Then in Questions 3 and 4 we move to two different populations since we anticipate this is where perhaps much or most of the discussion will be. Question 3 deals with neonates and pre-term infant patients asking (a) whether the efficacy endpoints chosen for Study 2 were acceptable, and if not, to please suggest alternative clinically meaningful efficacy endpoints for pathological gastroesophageal reflux in this age group.

(b) asks whether the specified trial design inclusion criteria, monitoring, and assessments are adequate or not, and if not, to please suggest alternative or additional criteria, monitoring, and/or assessments.

Three (c) asks whether the safety endpoints chosen for Studies 1 and 2 are acceptable and if not, please suggest additional safety endpoints.

And then 3(d) asks for both the neonates and pre-term infants and the infants from one month to 11 months of age for follow-up for at least 12 months, and so we're asking the committee: is the duration of proposed follow-up at six and 12 months after enrollment for developmental growth and safety assessments -- whether or not that's adequate, and if not, what duration of follow-up safety assessment is recommended?

For Item No. 4, we're talking about infants one month to 11 months of age.

Four (a), and these are basically repeats of the previous question: are the efficacy endpoints chosen for this study acceptable? If not, please suggest alternative or addition clinically meaningful endpoints?

Four (b), are the specified trial design, including criteria, monitoring and assessments adequate? And if not, please suggest alternative or additional criteria, monitoring and/or assessments.

Four (c), are the safety endpoints chosen for Studies 3 and 4 acceptable? And if not, please suggest additional safety endpoints.

And 4(d), is the duration of proposed follow-up at six and 12 months after enrollment for developmental growth and safety assessment adequate? And if not, what duration of follow-up safety assessment is recommended?

And finally, Question No. 5 asks about the pharmacokinetics and pharmacodynamic designs in studies that we've requested, specifically asking: are the study designs for the single and repeat dose pharmacokinetic and pharmacodynamic/pharmacokinetic studies acceptable? And are there additional and/or alternative assessments recommended for study of proton pump inhibitors in pediatric patients?

And I thank you, and we look forward to a good discussion.

CHAIRPERSON CHESNEY: Thank you, Dr. Raczkowski.

And for those of you who may not have heard, Dr. Murphy has given us permission to go until ten o'clock tonight if that's what it takes --


CHAIRPERSON CHESNEY: -- to answer all of these questions, but we can have our time moved to one o'clock, and we'll postpone this afternoon's meeting by an hour.

So let's start with the first question. Can the efficacy of a proton pump inhibitor for the treatment of pediatric patients less than one year of age be extrapolated from adults? Why or why not?

Dr. Nelson.

DR. NELSON: Intensivists are always willing to jump in. A question. I was impressed in reading through the materials about the differences in presentation, symptomatology, and the like within this population, particularly which I guess they're going by the term supraesophageal or respiratory.

My question then is -- to some extent follows from Dr. Hassall's, I believe, presentation that the hard endpoints that you suggested are efficacy endpoints that could perhaps be extrapolated, such as esophagitis.

So if you presume that the change in gastric pH has any impact on esophagitis, to the extent that you're advocating a hard endpoint, I would raise the question as to whether efficacy could be inferred once you've done the appropriate pharmacokinetic and pharmacodynamic studies.

If, however, you're looking at the supraesophageal and respiratory endpoints, it looks to me like you could not infer that since, in fact, that's not an adult presentation. So that would be at least my sort of working interpretation and question that would then come out of that.


DR. WARD: In the background information, I thought there was some nice description of physiologic changes that matured around six months of age, and it's unclear to me that the one-year cutoff is appropriate, that maybe a six-month cutoff might be more appropriate to define a different population.


DR. KAUFFMAN: I was impressed with that, too, and it reminded me we never do literature searches back beyond five years, rarely, and beyond ten years, never. But many, many years ago, when I was in Michigan, we did a study metoclopramide when it was a new drug in infants in the first year of life from one month -- two to four weeks was the youngest ones -- up to a year of life, who presented with GER with complications, not just spitting up.

And this was a randomized, double blind, placebo with a weak run-in on nothing, and then they were randomized to two arms. They either got metocloparmide or not.

And simultaneous esophageal gastric pH was our outcome measure at that time, and then we did secondarily parent recording at home.

But the thing that struck me about this study was that in infants up to about four to five months of age, we could not distinguish between placebo and active drug.

In infants older than four to five months, then we had a statistically significant difference using this prophenetic (phonetic) agent in terms of pH outcomes, and we speculated at that time that this was due to the fact that physiologic reflux and with frequent feedings in the younger infants was obscuring, washing out any difference in the pathologic reflux, and by the time we got to around six months, the babies we were seeing were true pathologic refluxers, and the drug was having a pharmacologic effect.

And it fits some of the other information that was described this morning. This maturation takes place around that time. So one of the risks of lumping one month to 12 months in one group is we're going to wash out, if there really is a change at around five to six months. We run the risk of washing out any efficacy that we might -- that might exist in that six to 12 month age group and not seeing it.


Yes, Dr. Blackmon.

DR. BLACKMON: I think one additional reason one should use some caution in this is the fact that there are so many different reasons for complicated reflux that occur in infants that do not occur in adults, and the reasons, particularly the neurologically impaired or those with anatomic disorders, would confound the efficacy issue substantially because it's not just acid reflux. It's the issue there.

CHAIRPERSON CHESNEY: Dr. Blackmon, would you support the six month cutoff that Dr. Kauffman and Dr. Ward were talking about for efficacy studies?

DR. BLACKMON: I would have no problem supporting six months for term infant. Quite honestly, I'm not sure where the breakpoint is for the extremely pre-term infant.

We have a whole population of infants now that we still don't know what their maturational course is, and that's by and large the infants of less than 26 weeks' gestation, and they are a substantial part of our morbidity in the NICU.

I would say if one could ascertain a reasonable break point for that group, yes, but for a term infant, I would have no problem with the six month.


DR. WARD: One of the important points that Dr. Blackmon made was these two categories, the child with esophtrialtresia (phonetic) and the neurologically impaired children that are frequently candidates for fundiplications and surgical intervention, and those children, I think, are almost universally recognized as difficult to treat.

Reflux is a significant morbidity for them, and I think we should actually think of those as a population that may warrant specific criteria for enrollment in trials.

CHAIRPERSON CHESNEY: So there might be two subsets of patients, the normal term infant maybe up to six months, and then the pre-term infant, and particularly those who have significant underlying disease.

Dr. Hassall.

DR. HASSALL: If I could just speak to a couple of the issues that were raised. I think that under the age of a year, as far as I can I determine, the only real hard endpoints are esophagitis and, slightly less hard perhaps, failure to thrive.

I see it being very difficult to have a good endpoint in the patient under one year of age, assuming that we are enrolling only patients with GERD, in other words, with GER disease, in other words, a complication.

So my response to Question 1 is I believe one can follow esophagitis or failure to thrive, but they are relatively uncommon. I mean, we do see esophagitis in the six, maybe four month old to 12 month old child, but they have to have pretty severe reflux disease.

So, again, we're talking about what's reality in terms of being able to recruit patients to these studies, and do we have enough? And certainly I would doubt that we have enough to break it into a number of subgroups.

The other issue that I'd like to address is the issue of the zero to 12 months. I'm not sure that that is important if we are only enrolling patients with GERD. We're not trying to enroll patients who are thriving, who are just vomiting, you know, upwards of 95 percent of whom will get better spontaneously. We specifically don't want to enroll those patients.

So we really only want to enroll patients with a complication, and once they've got a complication, then you can assess efficacy.


DR. GOLD: Actually I think Dr. Fink and then I'll go after him.


DR. FINK: My comment, I guess the concern I have as a pulmonologist and seeing the failure of NISN (phonetic) to correct problems is I really don't think we're dealing with GERD in the under six month old. I think we're dealing with feeding dysfunction, and it's a much more global issue. It includes maturation of upper airway reflexes, ability to swallow without aspiration, maintenance of the airway during sleep, and GE reflux often being one component of all of those elements of maturational and neurologic deficits.

But to cal lit GERD in the sense of gerd in older children I think is a misnomer. So I really think part of the problem is definitional, and Under six months really are talking about a feeding disorder or a feeding problem that may have GE reflux as part of its symptomatology.

And so I think the six-month cutoff does make some sense, and those are beginning to start out at that age, and the neurologically impaired child is probably a poor one to study even above six months of age because if you look at supraglottic manifestations, you're going to have to put in some very strict criteria to rule out aspiration from above because it's sure seen in a number of failures of NISN to completely dissolve symptomatology.


DR. GOLD: Okay. Two points. I think, first, it's easy to make the clear distinction -- I think this point was well heard -- that the patients with GI anatomic abnormalities really belong in their own special category. Those with neurologic injury belong in their own category, and then your, quote, unquote, normal.

But I'd like to sort of offer some provocative thoughts with respect to the issue of defining an age, and to use my esteemed colleague Greg Kerns' coin of words, I'd like three words: responsible, feasible, and applicable.

One of the things that I'd also like, and I said this to Victor in the break, is that this not stop here, that this be a continuing and ongoing dialogue.

What this wonderful set of references, I think, highlights is a different set of perspectives from different disciplines, that of ENT neonatology, pulmonology, gastroenterology, and pediatricians about an entity that really is still lacking clear case definitions, is lacking good epidemiology, is lacking good issues with studies with respect to its natural history.

We can't really come to a specific definition of the right age to do the cutoff when we haven't really defined the case definitions and then have followed that over time so that we understand what we're looking at at the six month, one year, two year, and ten year old.

And I think we need to think about it with respect to responsible, feasible and applicable. We need to think about it because in the end what we need to do are studies that we can go back to our clinicians, and those of us who are clinicians who are going to be using these drugs anyway, we're going to offer the information that's going to allow them to make appropriate and safe choices for drugs to use.

Secondly, for the parents of these children who -- my daughter had fairly significant reflux, both the destroying of the ties, but also the screaming at night -- and those that we're going to be asking to participate when we're giving them the informed consent form in these studies.

So I think that we need to think carefully about our cases, whether we're coming up with definable clinical correlates and objective, validated endpoints that then can be used in efficacy studies in these particular age groups.

And I think because of the advancement of technology and the fact that we are, you know, resuscitating premoids at 450-500 grams, we're dealing with a whole different set of populations that have a whole lot of co-morbidities that either need to be controlled for in a proper design or thought of in terms of contributing to the overall process of reflux.


DR. WINTER: Well, I would like to really commend and thank Hugo and Victor and their colleagues for focusing this agenda on a very important issue for our patients, and it's not because I have to leave early to go to my daughter's senior prom that I'm going to come to be somewhat definitive about my comments.

But I would propose to the voting members of the committee that efficacy studies in premature infants not be part of a PPI template, and I base that on the comments that Dr. Gold made, and I agree with what he said.

But apnea associated with GERD is controversial. As an outcome measure, it's affected by multiple factors, including CNS development, LES maturation, GI motility, feeding issues, cardiopulmonary disease, and the role of acid suppression in treating apnea is of questionable value.

And so I think that doing efficacy studies in this population is not feasible, and I don't think will give us the answers to those questions.

I think our responsibility to our patients and to their families is to understand the pathophysiology of the disease and to encourage the NIH and the Children's Digestive Health and Nutrition Foundation to support RFAs to answer these kinds of questions.

And probably more importantly, I think our role is to educate practitioners about evidence based medicine and to have educational campaigns to do that because I have a sense what's driving the questions that we're being asked is use and not benefit.

And so I think that we need to separate the question about industry sponsored template for PPI from the pathophysiology and the educational needs that our patients need to have.

So I would urge the committee not to consider efficacy in the premature infants as part of the PPI template, but rather to encourage other means of addressing these questions.

CHAIRPERSON CHESNEY: Dr. Winter, I'm not sure when you have to leave, but may I ask you a question? If we don't consider the use of PPIs in premature infants, what population or is there any population that you think we should look at efficacy studies?

DR. WINTER: Yes. I think that we should look at efficacy studies over a year of age. I think that children over one year of age -- reflux, I think, is a disease that begins some time in child -- adult disease begins sometime in childhood for many patients, and it's a disease that waxes and wanes, and the cycle of injury and repair over many, many decades results in complications of GERD in both adolescents and in adults.

So I think of the disease over a year of age in children may be the harbinger of sequelae of disease in older children. So those are the patients that I would consider efficacized to be critical in.

And, for example, in children over a year of age who have irritability, who are in pain, PPI therapy may be effective in those patients, and that's a population in which PPIs are being used, and it is possible to design studies using irritability or the evaluation of irritability as an outcome to assess efficacy of those medications, not in hospitalized patients, but in patients who we see in our office and in whom we use PPIs on a regular basis as gastroenterologists.

You have to exclude conditions such as allergy and food intolerance, which you can do by pH monitoring, because children who have reflux presumably will have some abnormality in pH probe studies, and that will also give you some degree of PK and PD assessment.

So I think that's a population in whom efficacy studies are valuable, but I'm not convinced that efficacy studies have a role at this point in time in children under a year of age.

CHAIRPERSON CHESNEY: May I just take the speaker's prerogative and ask you one more question?


CHAIRPERSON CHESNEY: You made the mistake of saying you were leaving.

DR. WINTER: No, I have until about 11:30.

CHAIRPERSON CHESNEY: I do a month of general pediatric attending every year, and this is the population that I understand the least about and the ones that get us into the most trouble, and I'm particularly intrigued by Dr. -- not the most trouble, but where we're just, you know, pulling things out of the air -- and I'm intrigued by Dr. Hassall's comment that they reduced their anti-reflux surgery from 50 to five patients in one year. That's phenomenal to me.

But I'm also struck by how well the anti-reflux surgery works. I mean, something is being repaired in these infants.

And I feel like if we don't address this issue now, it's going to be several years down the road where we still don't have anything for these infants, and that's maybe a somewhat emotional response, but you know, of everything that I see on the general pediatric service now, it's these infants that we seem to understand the least about.

And I wondered if that would factor at all in your decision just to look at efficacy over a year of age.

DR. WINTER: Well, I agree with you. I think that this is a question that certainly needs to be studied. I'm not sure that this is a question that needs to be studied by industry sponsored investigation.

I mean, I think that this is a very important question. It's a question that the NIH and foundations, such as CDH&F, which sponsor RFAs to answer these kinds of questions, should be sponsoring and should be asking these questions, and there should be well defined studies to look at the physiology and efficacy of these trials.

But I'm just concerned that the size of the studies are not going to answer the questions. The purpose of these studies is different, and I think that I'm just concerned that we're not going to get the information that we want to have by requiring this as part of a PPI template.

That's my motivation in saying the statement.

CHAIRPERSON CHESNEY: I understand. Thank you.

Dr. James.

DR. JAMES: I just wanted to follow up on Dr. Winter's comments, and I agree with him in that the efficacy studies are very difficult to do in the children less than one year of age.

But I do not think that relieves us of our responsibility to continue doing the pharmacokinetic and pharmacodynamic evaluations because we know that we can do those types of studies. We have done those studies in HT receptor antagonists. We can use the same type of templates to study the PPIs in the children less than one years of age.

So that at least at the end of the day we have the dosing information, and we have the developmental maturation information to be able to provide to physicians and to families.


I have Dr. Hudak, Raczkowski, and Gold, in that order. Dr. Hudak.

DR. HUDAK: I guess I'd like to take a slightly different tact to that. I think that the studies in the premature babies for efficacy do need to be done. Whether they're done as a part of a written request here, whether they're funded by an HMO or NIH or whatever, I think they desperately need to be done because there's no question in my mind that this class of drugs will be used with great frequency in neonates.

And to do that without any information on efficacy or safety, I think, is a mistake. We've gone down that path many time.

So as an advocate for our patients, I think that that information is critical. As difficult as it might be, you know, to design the studies, I do think that with relatively few number of patients you can have information as to whether or not the therapy is effective.

There is reason to suspend some disbelief here. I think that there's reason to think that it might be affected. As you point out, we don't understand very much about the association of reflux with apnea in a lot of these children.

I think there is some evidence that there is an association, although we can't get at it with the methods we've used thus far, but I think if you were able to demonstrate a decrease in those supraesophageal symptoms with the PPI class medications, you know, that would go a long way towards stimulating a lot of the investigations in terms of pathophysiology and whatnot that you allude to.

But I think practically speaking, looking at our patients, without studies this class of drugs will be used and will be used relatively indiscriminately.


DR. RACZKOWSKI: I actually have a question, I think, for Dr. Winter, but before I ask the question, I just wanted to rephrase Question No. 1 in a way that may facilitate some of the discussion.

What the proton pump inhibitor template asks for in children greater than a year of age is not formal efficacy studies. It asked for PK and PD studies, and the assumption is there that if you know enough about acid suppression from blood levels and from pharmacodynamic studies, that the disease of gastroesophageal reflux disease is sufficiently similar between kids more than a year and above to allow us not to have to redo formal efficacy studies in those kids that are greater than a year of age.

On the other hand, in kids less than a year of age, we've taken the approach that PK/PD is not enough; that if all you knew was about acid suppression of these agents in that age group of less than a year of age, that would not allow you to draw any conclusions about whether the drugs really work because the manifestations are very different in that age group.

And so I guess the question I have for Dr. Winter is: do you believe that there are specific differences between GERD in kids more than a year of age or so that would require us to do efficacy studies or if we know enough about acid suppression in terms of the PK and PD, is that enough?

Once we get the right dose, that gives us a certain amount of acid suppression. Would that be enough for that age group of more than a year of age?

DR. WINTER: Well, first, I agree with Dr. James about the benefit of PK and PD studies in all of the age groups. I think that that's very clear.

The question about efficacy over a year of age, I think the pathophysiology is similar. The clinical presentation is somewhat different in that children over a year of age may have different clinical symptoms that need to be assessed, such as growth issues that may be important.

And children between zero and one year of age, the outcome of irritability is a major factor that's different than adults, but I think that the pathophysiology is similar.

So that efficacy studies over a year of age, I think, adult data is extrapable. Between zero and one, I think that there are differences in terms of the clinical manifestations that we should be studying in terms of efficacy, and in premature infants we already discussed that issue.

CHAIRPERSON CHESNEY: Dr. Gold, you were next.

DR. GOLD: I actually am not sure that I necessarily completely agree. I think that we still don't know enough about manifestations in that over one to 11 year group to completely say that we can extrapolate all that is learned in adults to that.

I agree and would like to echo Dr. James' comments that I think there is the importance of doing the PK/PD in the less than one because at least with that we can say -- and safety -- we can say we can offer a safe dose. Whether or not it's effective is not clear.

And I think, you know, your comment about the fact that the fundo.'s (phonetic) work is an interesting point. Fundiplication rates, when one looks at the pediatric hospital information system, which is probably 32 children's hospitals across the U.S., have risen dramatically from 1995 to the year 2000 and, in fact, have grown exponentially even though the rate of GERD admissions, which is four percent of all hospital admissions, as any diagnosis in the year 2000, it has gone and exceeded that of GERD, particularly with the fact that the lapnissen (phonetic) now, which the first report was in '95, is available.

And yet you look at the literature, and there's a complete paucity, I guess -- that's a sort of an oxymoron -- but there are no studies that look at outcome or long-term natural history of the fundiplication and what you're doing long term with these children.

So I think that the surgeons are going to continue to do fundiplications, and those of us who would try to, you know, use appropriate, as Dr. Hassall pointed out, case selection in those patients that go to surgeons, we need to have good data that then we can use in terms of applying appropriate medical therapies and maybe non-medical therapies that will help our children both at the time and then long term.

CHAIRPERSON CHESNEY: Dr. Hassall and then Dr. Nelson.

DR. HASSALL: A couple of questions. Just to address the fundiplication issue first, there are very -- there are lots of data in the surgical literature about the success or otherwise of fundiplication in children, and while they may work acutely -- and I can give you these published data and summaries on them -- the longevity of fundiplication in all handicapped children, esophageal atresia children, and children without any underlying disease is astonishingly short.

The surgical studies go no more out than about five years at the absolutely maximum, with no physiologic parameters to determine their success or otherwise, and the failure rates within a year to two years are staggeringly high, you know, 30, 40 percent easily, and in the high risk groups, higher than that.

So I think we are really looking -- not that I don't refer patients for fundiplication, but we select them in the particular way that I mentioned earlier.

So I think that really fundiplication has a role, but I think that the degree of consideration we're giving to PPIs actually in many ways speaks to the failure of fundiplications, and even when it works, these children have some problems.

I'd just like to get back to Dr. Raczkowski's questions, and that is I echo Dr. Winter's comments fully. In the under one year old child, once you enroll a patient with a complication, it doesn't matter if 90 percent, 95 percent of children who are healthy get better by the age of a year or two years. We're only enrolling or thinking about children who need PPIs, hopefully, who have a complication.

And once they have a complication, and especially I think we'll find if we study those under one year olds, the great majority of kids with esophagitis and/or failure to thrive and/or chronic cough, et cetera, et cetera, are going to come from two groups: esophageal atresia and neurologic impairment.

And in our studies, upwards of 50 to 75 percent of all of the children, even in the older age groups, have come from those groups when we select out others.

So once we've got those children with esophageal atresia or neurologic impairment, I would extrapolate to the under one year of age from one to two years of age or three to four years of age or eight to ten years of age if they've got esophagitis and failure to thrive or chronic cough.

The kids under one year of age -- and I'm specifically excluding pre-term infants; I'm talking about zero to one. I think pre-term infants is a different discussion.

I would feel that one can easily extrapolate the pathophysiology and the consequences of reflux in the zero to one year old from the two to three year old, from the older child. And we've shown that PPIs in several studies, lansoprazole, omeprazole, many, many studies, long term and short term, can treat these.

As long as it's an acid related disorder, we've shown that acid suppression in adequate dose can work. So I would definitely propose assuming efficacy under the age of one year from not even -- perhaps it's too scary to assume it from adults, but from five year olds, from ten year olds, from 15 year olds.


Dr. Nelson.

DR. NELSON: That actually leads in nicely to the comment I wanted to make. The scientific discussion we're having has an underpinning of an ethical principle, which is that children shouldn't be exposed to unnecessary risk.

And if one could extrapolate efficacy, then you shouldn't have to do studies of efficacy that might involve such risk.

One concern I have is that there is, for example, five drugs on the list of PPIs that are used in this population, all of which are on the list of having received a written request. The question I want to put on the table is that, in fact, we should be willing to extrapolate efficacy from a study in pediatrics using the same disease and the same drug class to another study in pediatrics.

And it would concern me if we're, in fact, having the fifth or fourth or third company doing what one and two had to do. The first efficacy trial for the first drug should be applied to a modification of the written request for Drug 2, Drug 3, Drug 4, Drug 5.

That's how IRBs are going to review this. We're going to see what's labeled, what's available, what's being used, and just ask the question: do we really need to do this in kids for another one?

So I think that's something I'd like to put on the table that needs to be part of the discussion.


DR. FERRY: I think that my clinical experience is a little bit different from what Dr. Hassall mentioned. We certainly see a lot of children in the first year of life with neurological impairments, esophageal atresia and problems that lead to really severe reflux disease.

But we also see in our practice a lot of children who are not thriving, who are drying, are really poor feeders, irritable, all of the same spectrum that older children will complain of heartburn, and you know, to me it's the same disease.

So I don't think it's just these other complicating diseases that are the most common presentation in our own practice.

I think his point that we might well be able to extrapolate from older children to the one year of age I think is a really good point. I really think these children in every clinical sense seem to respond the same way a two year old, a three year old, a five year old does.

And we can document the fact that they actually have esophagitis. It may not be erosive. We can document pH changes.

I think the question to me really comes back do we actually need the efficacy studies in that group of patients.

CHAIRPERSON CHESNEY: Dr. Ferry, do you think we need any efficacy studies in children?

DR. FERRY: Well, I think certainly when you get down into pre-term infants, there I think that's a different group of patients totally, but I think, you know, if we knew the dosing -- I mean, my clinical judgment tells me these drugs have made a huge difference already, and there's a good bit of data out there.

I mean, do we need efficacy? I almost hate to say no to that. That seems like it's probably the wrong approach, but in fact, clinically these children respond the same way older children do. Even at three and four months of age, we have patients referred all the time that have failed all the standard positioning, taking feedings. I mean, you can take all 13 people in our group, and they are absolutely convinced that these drugs work.

And we have the endpoints, you know, to measure that already. We see esophagitis. We do end up scoping, you know, a number of these children.

I think dosing, you know, is important. I think to my mind efficacy, there's a lot of data out there that says these drugs work in this first year of age.

CHAIRPERSON CHESNEY: Dr. Ferry and Dr. Hassall, it sounds like you already have a wealth of experience with these drugs, and from your vantage point, the thing that you need is PK and PD information. Is that a fair statement?

DR. FERRY: One of the first studies I ever did was on tube feeding in children with failure to thrive in reflux because we didn't have any -- I'm older than most people here. So it goes back a long ways -- and we don't do that anymore at our institution.

This used to be standard treatment. Failure to thrive from reflux, you put them on tube feeding, small volumes. They gain weight. Their reflux gets better.

We don't have to do that at all anymore because of PPIs. I mean we just don't do it.

CHAIRPERSON CHESNEY: Can I just write down the dose you're using?



DR. HASSALL: Yeah, I think the studies have been done. I think we already know not just from personal experience, but from published studies that these drugs work in older children from one year up.

And so I don't think we need to reinvent, to rediscover the efficacy, that these drugs are efficacious.

I fully support Dr. Winter and Dr. James and everybody else who said that we do need PK studies because I see these as dosing and safety issues.

I don't see efficacy issues on the table for children who are in the age group we're talking about right now.


DR. WARD: It sounds like among the pediatric gastroenterologists there's relatively good agreement that the signs and symptoms of erosive esophagitis disease is similar in the young infant as it is in the older child. Would that be the group that there would be agreement that the efficacy is not needed in that group, excluding, again, the pre-terms?

DR. HASSALL: I'm sorry. Is the question that just --

CHAIRPERSON CHESNEY: I think the question was: would you both agree that efficacy studies are not needed in any age group which has -- and please correct me -- classic adult GER disease manifested as irritability instead of pain and some degree of esophagitis; that we don't need efficacy studies in children?

I didn't phrase that as well as Dr. Ward.

DR. FERRY: Well, no, if I understood the question, it was talking about erosive disease, and that's not the predominant disease in children. You can demonstrate esophagitis by biopsies. You can demonstrate acid reflux. I think erosive disease is actually not the most common form.

DR. WARD: Yes, that was probably a neonatologist misspeak.


DR. WARD: So I guess I would say esophagitis disease: irritability, pain, sometimes refusing feeds.


DR. HASSALL: Yeah, plain and simple esophagitis, histologic and/or gross, yes. But I would extrapolate and say that if a disease is acid related, then these drugs are going to work, and we already have efficacy and safety data with hard endpoints.

So, you know, we might debate whether or not respiratory disease is or is not due to acid at all or whether it's due to volume reflux. But if it's an acid related disease, we already know that these drugs work in acid related disorders, and we have pH studies to prove that, as well as other endpoints.

CHAIRPERSON CHESNEY: Dr. Wilfond, and then I have Dr. James.

DR. WILFOND: You know, looking at it from a point or perspective, I want to echo what Bob Fink had said before because I understood his comment to be in the opposite vein, that the issue for those children with complex problems, and that includes some pulmonary manifestations, perhaps some subtle neurological impairments, are sufficiently complex that it may be even harder to tell efficacy when it exists.

That's what I thought I heard you say, and I think you were trying to make a claim that even an attempt at doing efficacy studies may be challenging, but at the very least, I think that I would want to say that for that population, I think efficacy studies are necessary to sort out to what extent these types of drugs are helpful in that population.

CHAIRPERSON CHESNEY: I had Dr. James down. Do you?

Dr. Winter.

DR. WINTER: I think that what Dr. Hassall said is precisely the point from a GI standpoint, that if the disease is acid related and we know the right dose to suppress acid, which is a critical component, then we believe that the medications that we have are effective.

The question about asthma and, you know, other pulmonary disease is much more complicated because of the multi-factorial nature of the diseases. And you know, I think the question is not so much about PPI efficacy. The question is: are these diseases acid related?

And the question is whether or not that's an appropriate thing to include in a PPI template, and that, I think, is the essence of the question.


Dr. Spielberg.

DR. SPIELBERG: Yeah, I think it sort of gets to the heart of the whole thing. When we think about extrapolation of efficacy, we have to have an understanding of mechanism in order to be able to extrapolate efficacy. So clearly for the acid related issues that are clearly acid related, the issues of PK, adequate acid suppression, and safety and formulation so that you can accurately and appropriately give a dose are really the heart of the matter.

What I'm hearing from the discussion because I think all of us are worried about youth in other situations, and that includes both patient populations, such as the neonate, and other indications. I'm hearing a fair amount though that in terms of valid endpoints to design some of these studies, that we really don't have them, and that brings up several issues, not only a failed study potentially where there may be efficacy and we're just measuring the wrong thing because we don't have the science, but it also brings up ethical issues because if we're going to design studies with endpoints that we really don't believe in to enroll children in such a study when we really don't have confidence that that study is going to give us an interpretable outcome raises some real issues for me.

I agree with Harland that we need those data. We have an obligation to all of our patients in whom a drug like this is currently being used.

And I agree, too, that we have a long way to go to develop some of the endpoints from an NIH perspective or from a pediatric GI community perspective, to give us endpoints we can use, which may say -- and not to confound age populations and cornicity -- it may be premature to ask for certain types of studies until, indeed, we have enough understanding.

Are these acid related? If they are acid related, then we'll be able to extrapolate. If the data show that they are not acid related and they're still being used, then one has to question why the drugs are being used in the first place.

So there are two levels here. One is the desperate need to get the data, and there are a number of mechanisms which have been suggested today, and then the second is the issue and the confounder here of the incentives.

And just to make some comment about use of the Best Pharmaceuticals for Children Act and such, I think all of us agree that because, indeed, the incentives cover the moiety as a whole, this is a good opportunity to study conditions outside the adult situation where efficacy studies would be needed in unique pediatric diseases.

And I think this is one of the things that was in the back of everybody's mind, including Congress, to give a mechanism to insure the diseases outside adult diseases can be studied.

The flip side though is if we don't yet have tools to adequately do those studies or if they are questions about those tools, I think we then have to seriously consider whether that should be part of the template or go into something like an NIH mechanism which will provide those data in the long run.


Dr. Gorman, you had your hand up.

DR. GORMAN: I always dread speaking after Dr. Spielberg.

CHAIRPERSON CHESNEY: Sorry. Next time I'll ask you first.


DR. GORMAN: Thank you so much.

I always enjoy listening to my colleagues who look at the other end of the telescope. They get the people who have been screened by the parents and then the pediatricians and perhaps another specialist before the eventually end up in your special areas of expertise.

These drugs will be used for every spitter that comes down the line, every fat, happy spitter. I would be delighted to see an efficacy study with a high rate of failure so that the pediatricians in private practice will learn which groups not to use these drugs on because I agree that the dissemination of information for both successes and failure, if it is so targeted to only be the acid disease which makes up some fraction of reflux disease, then it will be meaningless because it will get generalized as it gets detailed out to the community as being a treatment for reflux.

And reflux is like pornography. No one can define, but we all know it when we see it. And I'm listening around this table, listening for hard output, hard endpoints, and I hear a few that I think we all agree on, and then there's a lot of very fuzzy ones that we don't agree on.

I think efficacy studies are necessary because it will show us our ability to define the conditions on the way in, as well as define our endpoints on the way out.

Thank you.

CHAIRPERSON CHESNEY: Dr. Nelson and then Dr. O'Fallon.

DR. NELSON: I guess my question would be: what is the mechanism currently for the dissemination of the negative results of such a study? If the clinical indications have defined our cases, presumably if it's not pH related, we would end up with a negative study. If it's negative, I mean, there are existing requests out there.

I didn't check to see if anybody has -- well, I think one has gotten exclusivity. So the question would be: was that study negative? Did it use a clinical case definition? And if it was negative, do pediatricians know it?

I'll confess I didn't check the labeling to see if that has been disseminated in that way, but has that bene published as a negative study?

Because this all assumes the negative study would get out into the general pediatric educational materials. So I guess that's a question of adequate dissemination.

Often negative studies just disappear and don't get published and don't result in labeling.


DR. O'FALLON: When I came into this, I was very concerned about the endpoint issue just on the basis of all the stuff that we got from the FDA, and today it made it even worse for me listening to the facts presented.

So I do think if you don't have good endpoints, there's no way to get a good study. So I think that is the major issue here.

But if you can agree that there are some useful, maybe not optimal, but useful endpoints, especially for the acid associated reflux, then I think that the suggestion of having the randomized withdrawal study is very good.

I think that probably comes close to being an optimal design because what's going to happen is you're going to be able to get at some estimate of what percentage of the population do not respond at all. They will never be randomized because the drug right up front doesn't do any good for them.

And the ones that do respond, then you can withdraw, and I am assuming you would switch to a placebo and do a double blind. I'm assuming that it would be that sort of thing.

But if you switched half of them to a placebo and continued the study, you'd get an idea whether it was the drug that was doing it or whether it was some other underlying thing, such as maturation that's going on.

So I think a randomized withdrawal study with a double blinded placebo deal would really help to provide a lot of useful information about what's going on.

CHAIRPERSON CHESNEY: And that moves us to the second issue, and I wanted to ask Dr. Raczkowski if he wanted more input on the first question.

Dr. Fink, did you have something addressing the first one?

DR. FINK: Well, Dr. O'Fallon, I guess, just raised a red flag in my eyes in terms of study design, which is it's well known with esophagitis that if you used a withdrawal of placebo withdrawal design, if you take children who are symptomatic at enrollment and you put them all on an effective acid blocking agent for eight weeks, you're going to heal the esophagitis in many of those children, and you will then get a false negative result because you'll withdraw them onto placebo.

And depending on the length of time they're on placebo, they may be asymptomatic even though the drug was highly helpful to them during the non-randomized run-in period because your eight weeks may heal their esophagitis.


Dr. Raczkowski, we haven't given you a definitive -- I mean, many, many concerns were raised, and I think we all share those. Do you want us to go on to number two and assume that there's some population or --

DR. RACZKOWSKI: Well, let me just make a quick comment. I think that the agency by and large agrees that for acid related conditions, that these are effective drugs and that, therefore, if you could find the right dose by doing PK and PD, that that would probably be sufficient.

I think that the concern is that they are oftentimes being used and for what may or may not be acid related diseases, and that was the intent for the request of the efficacy in those populations.

But I think the discussion has been very, very helpful.


DR. MURPHY: Would it be fair to say at this point that the discussion has indicated, as Victor just said, that for acid related diseases we don't need efficacy trials for any age group? Is that -- I'm trying to summarize what I think I've heard here.

And then when we get into the cutoff of under a year, what I thought I heard was that we really don't think that's a good cutoff. We felt that basically the diseases that we were discussing that we were concerned about really were the respiratory related, pulmonary related, other diseases that occur in the younger age group, and the issue is: what are those diseases? What are those endpoints that we're going to be looking at? And is the age cutoff six months or lower?

So that's what I've sort of heard thus far.

CHAIRPERSON CHESNEY: Dr. Hudak, maybe you could help us with this. Do you feel like there are situations in the premature age group in which we do need efficacy studies for these agents?

DR. HUDAK: I think the answer in my mind to that is yes. I think, you know, we all struggle with endpoints, but you come back to the situation of why is the clinician starting a premature baby on his medication. Okay?

The answer is not we've got a pH probe that shows the pH is acidic. It is not we've got impedance technology that shows the baby is refluxing. It is not that the baby is regurgitates formula on, you know, the bed.

The reason a clinician starts the baby on these medications is because the baby has frequent, serious, significant apneas, bradycardias, and desaturations. That is -- Bob, would you agree? -- I mean, that is the answer.

DR. WARD: That's what our survey showed. It was pretty staggering.

DR. HUDAK: Right. And they don't study to define whether it's reflux, whether reflux is present or not. So what I think would be good, and I think those are pretty hard endpoints that we deal with clinically, and if you were to demonstrate that this therapy reduced those episodes from six a day to one a day, that is a significant improvement.

I think while they're doing the study there are other things that need to be looked at in terms of mechanism to make it efficient and to make it the best study possible for our patients so that we have some idea of what we're doing, but I think, yes, efficacy studies are needed, and, yes, the endpoints are fairly clear, fairly reproducible, easy to assess and interpret.


DR. WARD: The problem I see with that is the complex causes of apnea and the multiple ways that may lead to apnea as an endpoint and the multiple diseases that may lead to apnea as an endpoint.

When I had read through everything, I thought that the withdrawal trial, the withdrawal design was not a good one, but if, on the other hand, you use apnea as the endpoint and you only continue to study those children who have shown a positive response, it provides enrichment of the sample population, and I think it can get to the answer then about safety and efficacy more effectively.

This is how the drugs are being used, but I think there will be almost a ten to one treated versus responder ratio. That is, I think there will be a lot of kids with apnea that will not respond, but we don't recognize that clinically.

CHAIRPERSON CHESNEY: Dr. Winter and then Dr. Hassall.

DR. WINTER: In terms of the children between zero and one and over a year of age, I think just to clarify what Dr. Murphy said, and I agree with her, that if we know that a disease is acid related or if a child has acid related disease, we can assume that the therapy will be effective, that there was adequate efficacy.

The challenge is identifying those patients in whom there's acid related disease and, for example, children who are irritable. Some of those children are going to have food allergies and they're respond to being put on an amino acid based formula, and their irritability will get better.

Some of those children -- but if you exclude those children and you identify children who have delayed acid clearance or who have esophagitis, then PPIs should be effective therapy.

The problem I have is the statements by the neonatologists about the use of PPIs in children who have apnea and bradycardia in the pre-term infants. Because what I hear you saying is you don't have any effective therapy, and so because you don't have an effective therapy and you don't have any idea of what efficacy outcomes you need to measure, that you use whatever comes to mind or whatever is available, and you're not practicing evidence based medicine.

And that may be the reality of what happens in the NICU. I understand that. There's a certain practical aspect of what you do, and sometimes I put patients on probiotics because I think its going to help their diarrhea, and it may or may not be effective, but I would like to hear you define, you know, how you would do a study that's going to answer that question because I don't think it's necessarily in our patients' best interest or the family's best interest to enroll patients in clinical trials of efficacy in pre-term infants for which there is no adequate outcome and for whom we're not going to get the data by doing those studies because of all the confounding variables.

If you have a study design that will answer that question, then I think it's reasonable, but so far I haven't heard that.

CHAIRPERSON CHESNEY: Dr. Gardener had a question for the group or comment.

Use the hot mic.

DR. PEREZ: Could you either come to the podium or use this other mic? Apparently the sound person walked out on us.

DR. GARDENER: Proton pump inhibitors have been available for approximately 20 years, and there's a great deal of intellectual fire power and expertise from the pediatric GI community on the panel today, and my question is: why haven't you answered these questions if the questions are so important?


DR. GARDENER: Now, one possibility is maybe suitable methods don't exist to address these very important issues and to the extent that's your answer, to what extent do you want to commit pharmaceutical and biotech companies to conducting studies for which suitable methods don't exist.

On the other hand, if your answer is you've got a lot of terrific ideas and you believe they are good ways to address these issues, but you can't get funding, then to the extent you think that's the answer, then it might be appropriate to focus on given adequate funding, which is really what we're talking about here -- the funding won't be an issue -- how would you best want to design the study.

DR. WINTER: Well, I don't want to get going on why we don't allocate resources to children in this country because we'll be here until past ten o'clock tonight, but you know, I think that there's not been a lot of interest either from industry or from the government in terms of supporting clinical trials in children, and there are a lot of reasons for that.

It's changing now, and I think it needs to change quickly because we need to do these studies to get these data for these patients, and, you know, hopefully that's one of the outcomes from this type of a meeting.


DR. KERNS: I'd like to question Dr. Hudak, if I could, and please forgive me. I'll try to phrase this without dealing with the sensitivities of neonatologists.

When you as a clinician make a decision to commit an infant with apnea and bradycardia to a medicine that modifies gastric acid, what is your goal?

Now, let me answer what I think your answer is. Because you believe it's less onerous for that baby to aspirate an acidic fluid into their lung than it is a nonacidic fluid.

These drugs do not have any impact that I know of on motility, and so the driver for the decision is always, in my mind, what it does to gastric acid.

Now, maybe Dr. Ward has some data on showing that changing gastric acid impacts the amount of time somebody refluxes. Am I missing the pharmacology link in terms of mechanism?

DR. HUDAK: Let me go back and clarify a couple of things. One is that, first of all, I'm not for Dr. Winter. We're speaking for the general neonatology community. I don't think that Dr. Blackmon or Dr. Ward or I are necessarily representative in all aspects of that community, but we just deal with reality as we see it.

With respect to your particular question, you know, on these drugs, I think that the neonatologists around the table would not use these drugs in a baby who had apnea and bradycardia because we have no efficacy data, and we, the people around the table here, tend to be therapeutic nihilists and to practice evidence based medicine.

The reality is that I think a large number of our profession are perhaps more enamored by the potential promise of the drug, and they're also seduced by the possibility that they could do good for their patient maybe by using this drug. We tend to be more restrictive.

In terms of the study design, clearly it gets back to the patient selection issue that I mentioned to begin with. I think that the criteria for enrolling premature infants in an efficacy study will clearly be persistent apnea, bradycardia, desaturations that are unable to be managed by standard therapy, together with some evidence, preferably, actually exclusively by pH probe that the baby is having acid reflux. Otherwise, it's really impossible to justify using a PPI agent with any rationale that that's going to have any efficacy.

So I think if those criteria could be met, I think an efficacy study could be done whether it's a traditional placebo controlled or whether it's a run-in, randomized withdrawal. I think both have their positive points, and I think that one could get some answer.


DR. WARD: I would disagree with that. The other aspect is -- what we hear on rounds frequently is a child having severe apnea needing to be stimulated or bag mask resuscitated, and it follows an emesis, and that clinical scenario plays out a lot.

And I think to go back to Dr. Winter's comment, if you designed a trial in which there was a run-in period and you then withdrew only in those infants who had shown improvement in the symptomatology that you were associating with reflux and esophagitis, then I think you could do an efficient trial.

I think there will be a large number during the run-in period that do not show a response.

CHAIRPERSON CHESNEY: Back to Dr. Murphy and Dr. Raczkowski.

What I think I'm hearing is that we don't need efficacy studies in children for a disease which is clearly acid related, but we're not exactly sure how to define always clearly "acid related."

But what I do hear is that there are two to three populations where we don't know whether preemies would be, with all of the manifestations that we hear about, would benefit by having an efficacy study with these drugs, and also the infants with esophageal atresion and neurologic disorders, that we might benefit by having efficacy studies there.

And I'm wondering if other people would comment on whether I've totally misheard this, and maybe then we can move on to potential study designs if these are populations in which efficacy studies might be done.

Dr. Hassall.

DR. HASSALL: Dr. Chesney, I was actually making the point with esophageal atresial and neurologic impairment that the studies have been done in the two to three year olds, eight to ten year olds, and so I'm proposing not redoing those efficacy studies.

But I wondered if I could just address a couple of the points that have been made by other speakers.

Just a general comment, first of all, that acid suppressing drugs work in two ways. They don't just work by treating purely acid related disease and changing the pH. They decrease your 24-hour intragastric volume.

So if a child secretes about one cc per kilo per hour and an adult about maybe two to two and a half liters a day of gastric secretions, if the pylorus, the anti-pyloral unit is then presented with a low gastric volume, intragastric volume, that will indirectly facilitate gastric emptying, and actually this has been shown in a study in adults in Gastroenterology about two years ago.

However, I really wanted to focus on the issue of studying the pre-term or acutely sick children. I think we already have a safe drug for treating acid related disease, and that's IV renitidine, and if you can show that IV renitidine causes a change in intragastric pH and that is accompanied by a decrease in ABCs, in apneas and bradycardias, then I'm not sure that we need to trial in new drug because we know that renitidine is safe in that age group.

As Dr. Hudak pointed out earlier, he reduces when he's on service the drugs perhaps from 15 to ten drugs, but we're nevertheless dealing with an extraordinary number of variables, and I think to extract from that drug effect that we can attribute to PPI is going to be very difficult, not to mention the other conditions that affect pre-term infants.

So I'm not even sure we need a new drug for this, but even then, if we document apneas with pneumograms, it's extraordinarily difficult in my experience and from my reading of the literature to even relate that to an antecedent reflux event.

So I think we're actually dealing with two common circumstances which overlap, and I would think it would be extraordinarily challenging to design a study in pre-term infants, all sick newborns, that would actually answer the questions at hand.

And so in these circumstances, I really don't find an answer for a useful endpoint. I think there are just too many confounding variables.

DR. WARD: Could I just respond to the issue about renitidine?

There are some neonates who have demonstrably or measurably low gastric pHs in whom very high doses of renitidine are ineffective at raising that pH, and in those infants, they do respond to PPIs.

So there is still a subset of neonates who will not fully respond to the H2 blockers.

DR. HASSALL: So are those published data?

DR. WARD: Don't know. It's my personal experience. I don't know what Mark's is.

DR. HASSALL: No, no, no, just in terms of saying that they didn't -- I mean, we know that tolerance does develop to IV renitidine, at least in extreme short bowel syndrome in published publications.

But if you're saying that sometimes renitidine doesn't work, but PPIs do in newborns, but this is not on the basis of publications, right?

DR. WARD: No, no. It's just some clinical experience.

CHAIRPERSON CHESNEY: Dr. Spielberg, and then I have Dr. Fink and, I think, Dr. Gold, you had a question a way back, and I didn't write it down. Dr. Spielberg.

DR. SPIELBERG: Following up on the issue of what we know and don't know in terms of designing a trial, Dr. Ward, you sort of indicated that if you just took all apnea kids, maybe ten to one, other etiologies or somewhere in that neighborhood, do we know enough about stratification, say, methylxanthine resistant, et cetera, et cetera, to make any kinds of reasonable judgments of what proportion of the patient population we would define after that would likely to have an acid related mechanism because that has immediate implications for how you design the study, how you power it, how many patients you're going to need, et cetera, et cetera.

If it's still a very high, false rate of patients who are likely to respond even in an enrichment design some people would have responded to placebo anyway. So the numbers become extraordinary, and you really wonder of that population do we currently have the technology to define any better those kids who are really likely to respond to an acid expression mechanism.

It's a question to the neonatologists because, I mean, in terms of study design, we've got to have that if we're going to make any kind of rational approach designing a study.

CHAIRPERSON CHESNEY: Dr. Blackmon is going to respond for the neonatologists.

DR. BLACKMON: Well, a suggestion. One additional criteria for entry might be a history of recurrent infiltrates on X-ray not otherwise explainable.

We do have that phenomena in pre-term infants. I would say the sequence of changing the feeding, usually advancing the volume, increasing the handling, sudden emergence of these phenomena of infiltrates, and episodes of apnea and bradycardia that are very profound and frequently associated with emesis, but that is a small population of patients.

In my experience in a unit that admitted about the range of 100 to 120 infants a year in the less than 1,500 gram birth weight category, we might encounter that two or three times.

CHAIRPERSON CHESNEY: Dr. Fink, you had one?

DR. FINK: Well, I guess my comment -- it addresses a little bit Dr. Spielberg's concern. The other approach would be to be very empiric and do a randomized controlled trial in the use of PPIs in a selected group of premature infants to see if it decreases their time on oxygen, decreases time in the nursery, decreases the incidence of apnea. Because I don't think we can define the exact mechanisms easily by which all of these will occur. Yet they occur commonly enough that the potential of looking at this as a therapeutic intervention might yield interpretable results, and you would at least have definable endpoints.

DR. SPIELBERG: The question I still have though if you took all comers and only two or four out of those ten had a mechanism that at all possibly related to this, you'd never see it, and you'd lose the opportunity to actually define those patients who would benefit just because of the numbers.

And I don't have a good enough feel in today's nursery situation what the expectation would be, whether it's going to be one out of ten kids that's going to really respond to this or two out of ten or maybe eight out of ten, and that's what I'm trying to get a gestalt for.

DR. FINK: I guess as a pulmonologist, things that have been demonstrated it is clear-cut that acid aspiration is far worse than nonacidic aspiration. So if you're looking at premature lung disease in a global sense, you could say suppression of acidity in premature infants maybe of some real long-term benefit in terms of their overall pulmonary status, including apnea feeding and lung development, and it would be at least a tenable hypothesis with measurable outcomes.

CHAIRPERSON CHESNEY: And an infectious disease person would worry about intestinal --

DR. FINK: Sure.



CHAIRPERSON CHESNEY: I have Dr. Gold and Dr. Luban next. Dr. Gold.

DR. GOLD: Lest we forget the advances that have been made in this, again, as an IRB member, Vice Chair, I think I should raise this from an ethical standpoint, too. Let we forget the advances that have been made by clinical efficacy studies in a lot of other disciplines.

We need to not completely dispel the fact that doing the right thing for our patients. We don't completely exclude efficacy studies. I actually really appreciated, Dr. Gorman, your comment as the clinician out there in the trenches in terms of what data is going to be important. When we talk about what we're being responsible for, what are we going to give information that's going to go back out to the community physician who's got to deal with these parents so that they're giving safe and effective therapy to treat diseases.

The other thing that you have to realize is that although we've been speaking sort of from a narrow focus, at least as gastroenterologists, I mean, there are acid related disorders that result from acid refluxate into the lower esophagus that have manifestations outside.

Neonatologists are talking about apnea and bradycardia. I think, Dr. Fink, you've been alluding to other things, and that, again, thinking about careful case selection and appropriate efficacy studies where in those specific disorders where adequate acid suppression actually can be a very effective and safe mechanism for preventing those.

So I think we need to think about those as well in terms of how we're selecting out our populations by completely eliminating efficacy studies or before we do that.


DR. LUBAN: I was just wondering if the neonatologists could comment at all about the use of something like a SNAP-2 or a modified SNAP-2 to use as a clinical efficacy tool.

DR. WARD: You mean just using the acuity tool?

DR. LUBAN: Like a modified acuity tool later on.

DR. WARD: I think, again, it's too nonspecific, and I think, again, back to Dr. Spielberg's comment earlier, is that if you begin with a group of infants with apnea or apnea and suspected reflux and during the run-in period you only continue those infants in the trial who have a positive response to your intervention, that degree of enrichment makes the trial actually, I think, feasible, Steve, because those will be the only ones that continue on into the detailed monitoring during withdrawal or continuation.


DR. WILFOND: I had three comments on three related issues. The first is this question of whether or not the efficacy studies are needed, and I think I've heard two very conflicting points of view. The first is that we don't need them because we already know that they're efficacious, and the other one is that we don't need them because we can never find out whether they are efficacious.

And those are two very, very different perspectives, and we need to -- so I guess what I want to do is focus on at least for those groups where we need to know about efficacy, but it's hard to do. AT the very least in addition to the premature hospitalized population, I would want to remind people about the category of those infants between one and 11 months of age, whether they're children with chronic lung disease or the child who comes into the general pediatric floor because of recurrent wheezing, and often it's blamed on reflux and they're put on anti-reflux meds.

I think that's a population where we are in need of guidance. We do things without knowing what we're doing, what we think we do.

The challenge though, and this is my third point, is that it really is hard to measure this, and I completely agree with the people who are concerned and used the word "endpoints" euphemistically to mean we can't measure it because I think those -- and whatever the endpoints are, they are difficult to measure.

And the thing I want to get at is just if we're talking about things related to apnea, apnea is a very subjective measurement, whether it's an observation by a nurse or by a monitor, and I think the details we have to grapple with, but that's not a reason not to say that we shouldn't try to figure out who to do it.


DR. O'FALLON: For what it's worth, listening to this discussion, it sounds to me like the children less than a year do need to be studied, but it sounds like they need to be stratified as from one month to six months and then seven to 12 or something like that because it does sound -- the things that we've seen, there's something goes on at about six months, and you're going to have to look at them differently, separately.

DR. WARD: Can I make one observation about the lack of correlation between apnea and reflux as measured by pH probe? And that's the chemo reflex, to invoke that takes a tiny volume of assets that may not always be detected during a pH probe study.

And if you look, however, at children with frequent apnea and demonstrated reflux, whether the two have correlated or not, many times acid suppression reduces their global apnea counts, not in every study.

So we may not have the one-to-one correlation, but it may be our tools for measuring that.

DR. FINK: Can I just make a comment? There is a tool that exists, the Tuttle test. If you take diluted hydrochloric acid and stow it in the esophagus and you induce apnea, then you know you have an acid sensitive infant, and it's an old test. I don't think anybody does it anymore, but it does exist, and it actually has published data that looked at that exact question.

CHAIRPERSON CHESNEY: What concentration do they use?

DR. FINK: Tenth normal.


DR. FINK: Yeah.

DR. HASSALL: The Tuttle test was the predecessor of the 24-hour intraesophageal pH study. The chemo or regal reflex induced by acid reflux was actually only described in cats in a study -- not by anybody called Cats, but in cats, the animals.


DR. HASSALL: By Steve -- by Tuckman and Steve, who's the CEO of CHOP (phonetic), Steve.

PARTICIPANT: Alchava (phonetic).

DR. HASSALL: Alchava. Thank you.

By Alchava and Tuckman. This is, you know, in the early '80s. So the Tuttle test actually is not a provocative test. I guess it could be for inducing respiratory disease, but, in fact, to the best of my knowledge, it just was to find pathologic reflux, and it was filled with problems because a child could cry and they'd get reflux. If you put a lead hand or a non-lead hand on their belly, they would get reflux.

But I'm not aware of provocative studies that try to induce bronchospasm with the Tuttle test or with the Bernstein test, rather.

DR. FINK: It was actually looking at apnea, central apnea induced by it, and I think it may have been Dennis Nielsen when he was in Utah back in the early '80s. I think it was Nielsen who actually did publish that description.

CHAIRPERSON CHESNEY: One of the interesting things that I think we heard from Dr. Gardener and from Dr. Winter is with respect to the respiratory manifestations as an acid related phenomenon is do we want to ask pharmaceutical companies to answer this question for us or is this something that we should do with other funding to determine if there really is a relationship.

And I must say I was pondering that same issue last night.

But, Dr. Murphy and R. Raczkowski, I need some guidance here. I feel like we've spent a lot of time trying to answer whether efficacy studies are needed, but I think it's been very helpful and very important, and I'm not sure how we can go on until we settle that issue.

DR. RACZKOWSKI: Well, I think the discussion has been very helpful, and I don't think we need to spend any more time on Question 1, but are you saying that you feel -- if there is a need -- what I would suggest in terms of answering the subsequent questions is just assume that efficacy studies are necessary in this age group, and how would you go about answering this question for the respiratory and supraesophageal manifestations of these conditions?

CHAIRPERSON CHESNEY: So if we suspend our questions and accept that we're not exactly sure in what population we need efficacy studies, but if there are some identified populations --

DR. RACZKOWSKI: Right, exactly.

CHAIRPERSON CHESNEY: -- for example, maybe the premature population, then we can go on to Question 2. Is that a fair statement?


CHAIRPERSON CHESNEY: All right. So let's move on to Question 2, which is if we can agree at some future point that efficacy studies are needed in children, is the proposed placebo controlled treatment withdrawal design acceptable?

And several of you have already referred to this, but comments, questions? Dr. Wilfond.

DR. WILFOND: I'll start off with perhaps something I didn't make entirely clear in my presentation. You know, I do think that the notion of having a withdrawal or escape clause is really very valuable in terms of protecting kids from harms.

But I think the challenge, and this is what I didn't say before, is to define exactly what those withdrawal criteria would be. You know, are we talking about the frequency of apnea? Are we talking about recurrence of pneumonia?

I think we have to be very clear on what it is that we are regarding as failure for that withdrawal criteria to work.


DR. NELSON: You know, as described, I think, in the template written request, randomized withdrawal study from my perspective looks good. The one questions I have is the extent to which designs sort of move beyond the written request, particularly when it begins to include invasive endpoint measures that are really different than the respiratory or supraesophageal.

IRBs struggle, particularly if they're careful about doing what Ben referred to as the component analysis of risk when you've got invasive endpoint measures that are not normally performed clinically, and if pediatricians or pediatric gastroenterologists are not normally, for example, doing follow-up endoscopies, the argument then that there is direct benefit is felt to be, in fact, false because if there was going to be benefit, you would have been doing follow-up endoscopies at that time anyway.

So the risk assessment of those invasive tests are important.

Absent that in the current design, to the extent it's looking at apnea and bradycardia, which is not using invasive endpoint measurements, I don't see anything difficult with the design, but the written request is somewhat permissive in using languages such as "may" or "might" and the like to where it wouldn't exclude adding an invasive outcome measure, which many IRBs would, in fact, not approve given that it wouldn't be done clinically.

So I guess that's to say I would support the way it's written, but I would even strengthen the writing to say that, in fact, efficacy endpoints that are not necessary ought not to be included in studies where it's, in fact, beside the point of the direct primary outcome measure of that particular study.

CHAIRPERSON CHESNEY: Dr. Gorman and then Dr. Fink, Dr. Santana.

DR. GORMAN: The withdrawal design in this particular entity suffers, in my mind, from several possible failure points. One is maturation. Two is something for the acid related diseases, healing can occur and, therefore, would mask the effect.

In fact, the withdrawal methodology suffers from all the flaws that the crossover design suffers from, and I think those have been well summarized in one of our International Council on Harmonization documents, where they actually define the concerns about crossover studies.

Having said that, the population that gets to the point of the withdrawal study has to be very enriched in the sense that I would like those people to have been demonstrated to have tried alternative therapies prior. I don't want this to be a naive group of individuals, infants who then start on this agent initially, and therefore, I think the determination of the inclusion and exclusion criteria is probably much more important in this particular design; that these people have tried feeding manipulations, allergy manipulations.

Perhaps at least for the acid induced things, renitidine is another alternative prior to being put on the protein pump inhibitors.


Dr. Fink.

DR. FINK: I would like to reinforce Dr. Gorman's remarks, but also add that I think any written question of the agency would probably be premature prior to pilot feasibility studies of the endpoints being included in the written request having been performed because I think what we're really seeing here is a lack of pilot and feasibility data, and I don't know how you can actually ask for a study to be performed if you don't have some pilot and feasibility data on the proposed endpoints.

Dr. Santana.

DR. SANTANA: Well, just a general comment that I was wondering whether the study design issues might be different in the neonatal population versus the older population in terms of the population at risk and the confounding factors.

I was impressed by the discussion with the neonatologist this morning trying to define the endpoints, how that population is not very homogeneous, whereas I have always thought in a withdrawal type study you really start off with a population that's very similar, very homogeneous, and then it allows you in this initial period to define the benefit very clearly.

Now, I'm not sure that the neonatology population with all of the risk factors that we've heard this morning, whether that study design would benefit them, that a different, alternative design, standard placebo, up front control trial without the withdrawal phase may be more appropriate for that population because of the endpoints there, whatever you define, if it's apnea or bradycardia, can be observed very quickly in a very short period of time, and you minimize the risk to those patients getting therapy for a long period of time before the actual washout and randomization to the placebo.

So just a comment in terms of study design for the different population in terms of age groups.

CHAIRPERSON CHESNEY: Dr. Wilfond, I'd like to hear your response to that, and then Dr. Blackmon and Dr. Ferry.

DR. WILFOND: I just went to get a cup of coffee and I didn't hear what you said. I apologize.

CHAIRPERSON CHESNEY: I think what Dr. Santana commented on, that the withdrawal design is most applicable to a homogeneous population, and that what we heard from the neonatologist is that this is not necessarily a homogeneous population. Is that --

DR. GORMAN: Well, your withdrawal design issue is that you start with a fairly uniform group, and then at the end of that period, you define the benefit or not benefit, and people get randomized to continue or placebo.

I'm concerned that the neonatology group of patients is so confounded by so many other medical problems that these patients are having that if you allow that prolonged period of initial therapy for everybody, that I think you're actually exposing patients to a drug that is ultimately of no benefit.

And so I want to shorten that period as quickly as possible by not allowing that withdrawal design up front.


DR. FINK: Well, I think it might be worthwhile to clarify that. As best as I can tell, there are two components of the design. The first part is the initial run-in period, in which everybody is on the drug.

Additionally there's the issue of during the placebo controlled part of having very specific criteria for withdrawing a period from the study, and I think you could separate those two questions out. So one could envision a placebo withdrawal study in which there was on run-in period and in which you just took people and put them on either active or placebo and then still had your stopping rules.

Although I think that your other question about the heterogeneous populations, I think, is important because you need to be able to identify the types of patients in which the drug was helpful, and if the population was too heterogeneous, it might work in some subgroups and not others.

So I think we would have to be clear about what the right groups were.


DR. BLACKMON: Before Dr. Ward left, he and I explained a couple of ideas that I'd like to put out that may address this issue.

When you deal with apnea in a pre-term population, it is multi-factorial, and that's one of the problems in trying the design. But, in fact, apnea of prematurity that is maturational in terms of respiratory drive and many reflexes tends to subside in the bulk of pre-term infants at about 36 weeks' corrected gestational age.

And by what we have most recently learned in a very large study, it's virtually gone by about 43 to 44 weeks, corrected gestational age. So that if you designed your group to enter those infants who are symptomatic, and you can define your symptom complex, at 36 weeks corrective gestational age and their exposure to the treatment was within that window between 36 and 44, preferably not that whole time, but some portion of that time, and the randomization to placebo control occurred only in those infants who actually responded by a change in their apnea symptomatology, I think you would then get a very nice study group in which you could say the PPI really did have an effect or did not have an effect.


Dr. Ferry and then Dr. Nelson.

DR. FERRY: My comment was really related more to the children probably from zero to one year of age or perhaps older, and that has to do with the run-in period itself.

Certainly if you maintain that run-in period I don't know how long, four weeks, six weeks, certainly eight weeks, you're going to produce healing that you'll no longer be able to see a benefit. So the critical piece of that would be, you know, what is a reasonable time to keep patients on the drug. Is that two weeks? And, you know, what is the basis for that? Is it a steady state of the drug? Is it some early symptom relief that then you can see, you know, worsening symptoms again?

It gets to be very tricky, I think, what that actual run-in period would be.

CHAIRPERSON CHESNEY: Dr. Nelson and then Dr. Raczkowski.

DR. NELSON: I guess just one quick comment just in response to that. The esophagitis would be an efficacy endpoint through that we've already decided would be unnecessary. So it's not clear to me that the issue of healing would necessarily undercut the study, although it raises a question for what the mechanism might be for apnea and bradycardia.

But, you know, my question goes back to Victor's comment about the differences between a standard placebo design and a randomized withdrawal. If there's evidence that acid control decreases apnea and bradycardia, and I guess by not having looked at the neonatal literature for a while on that point, we not only have to -- if there is, we not only have to consider the use of proton pump inhibitors, but the use of renitidine and other agents in deciding whether it an be approved under 5052.

In other words, you have to consider the risks and benefits over the alternatives, which is not just the alternatives in the trial, but the alternatives that that child would or would not receive outside of the trial.

You know, if there is no evidence -- and part of the discussion is do neonatologists do evidence based medicine or not -- but if there is no evidence, I guess then we could debate that.

But if there is evidence that renitidine is helpful, then I think you would have to design a trial that would basically only enroll infants who failed both the standard positioning, all of the various things that have been discussed about as well as failed renitidine before you then went on to take that population and put them in a proton pump.

Having said that, if that's the population that's already failed all of those therapies, I don't think there would be a problem in designing it as a standard placebo controlled trial. The assumption in designing it as a randomized withdrawal is that acid control is effective.

DR. SPIELBERG: Can I ask Dr. Murphy and the GIT what is the current status of H2 labeling specifically with respect to newborn?

I know there have been studies done on some of these compounds, but what is the status with respect to current label and data for newborn use?

DR. RACZKOWSKI: Yeah, I think renitidine has labeling all the way down to birth, and I'm not sure about famotidine.

DR. GALLO-TORRES: It goes all the way down to zero to one month.

DR. RACZKOWSKI: Okay. Well, we're sure that renitidine has labeling down to birth.

DR. SPIELBERG: And in that context, is there anything about what we're talking about here today?


DR. SPIELBERG: The use indication.

CHAIRPERSON CHESNEY: And what is the labeling for renitidine?

DR. RACZKOWSKI: Okay. What was requested of renitidine is pharmacokinetic and pharmacodynamic information down to birth. Renitidine does have labeling for treatment of gastroesophageal reflux disease, but that was at a time when the written requests were being written without complete appreciation that the efficacy may not be extrapolatable just on the basis of PK/PD data alone.

And so we've taken a shift in our approach, particularly the powerful proton pump inhibitors, to request efficacy studies in kids less than a year.

I'd like to address a couple of comments, I think, that were made. One has to do with the heterogeneity of the treatment groups, and I agree that if a population could well be defined up front, that would be the ideal way to go.

But there's a couple of things in this trial design that help handle heterogeneity. One is, as has already been discussed, is that when patients are enrolled in the run-in phase, it's the patients who continue to the randomized withdrawal who are the patients who appear to be responding.

So it's an enriched population, and by definition, it's a less heterogenic population. Another way that the heterogeneity is handled is just through simple randomization, and we certainly acknowledge the fact that if you have a heterogeneous population, that will require larger sample sizes to get the same answer than less heterogeneous ones.

But I don't think that the study design per se is an issue with regard to heterogeneity. It's more of a function of can you identify the population that you want to identify to enroll in the trial, and one way of doing that is through the enrichment phase of the randomized withdrawal, which is the run-in.

And I'm not sure I completely understood Dr. Nelson's comment about renitidine. I would just simply say for other blockers, I would just simply say that these written requests are brought out and are not as detailed as a protocol might be, and that use of other agents like H2 blockers could be written and that sort of thing, and whether they should be excluded up front or whether they should be controlled in some way in the protocol or in the study can be handled in the protocol, not necessarily in the written request.

So those sorts of issues can be handled in another form when we actually review the protocol to exclude confounding factors.

CHAIRPERSON CHESNEY: Could I ask for other comments? Dr. Nelson mentioned a standardized placebo controlled study as being an alternative if everything else had been tried and was unsuccessful. What would people's response to that be?

Dr. Danford.

DR. DANFORD: It occurs to me that if we insist on trying other methods for a period of time to make sure that the patients are unresponsive to standard methods, as good an idea as that is and as much safeguard as that gives the patients, that does chew up valuable time which will be further consumed in the run-in phase in a condition that sounds to me as though it spontaneously disappears over a fairly short period of time.

And I wonder if we would be losing the opportunity to identify a clinical effect if we were too restrictive in our inclusion criteria to the point where we would be trying all of these other things first.


DR. NELSON: I guess I agree with your procedural concerns, but in evaluating as I might, looking at it on an IRB, I would just say, "Well, I guess sorry about that."

If, in fact, equipoise is required, meaning you can't put a child into a study that places him at a disadvantage against whatever treatment they may otherwise receive, what clinicians are doing or gastroenterologists are doing in taking care of these patients is relevant, and whether they've failed traditional therapy would be relevant to that.

I'm somewhat dependent. I haven't heard a lot of evidence to say we know what we're doing in this very young age group, and if that's the case, equipoise does exist.

But to the extent that we're trying positioning all of those other things at least should have been tried and failed if you're going to do a standard design, enriched design as an add-on; I think would be also the point that was made earlier, is you presumably were adding on PPI to these other standard therapies that I think most pediatricians would provide.

Otherwise, I would argue it's not in compliance with the 5052 and cannot be approved.


DR. WILFOND: It would seem to me that there's an equal amount of skepticism for renitidine, as well as proton pump inhibitors, in terms of the ability to effectively treat apnea and bradycardia. So it's not clear to me that on that issue it's essential to try one way or the other.

But, Skip, the question I had for you is in terms of your talking about more standard placebo control trials, again, I was still unclear whether the part that you were suggestion is not having a run-on period or not having the withdrawal part later on, or both.

DR. RACZKOWSKI: I think you've defined a population that has failed to respond with what would be considered appropriate evidence based interventions and not just whatever we're doing because we think it works.

Then for that population equipoise exists to then make an intervention because you don't have any other intervention that's been shown effective. So that's not an enrichment. That's just saying you're enrolling infants who have failed other therapy.

Now, I agree there's a problem if development gets better in three months and it takes you two and a half months to fail other therapies, but that's a practical issue that would have to be looked at.

So it's neither an enrichment nor a withdrawal. It would be selecting a population for which you truly in equipoise about -- in other words, they failed therapy that's been shown effective in other settings.

CHAIRPERSON CHESNEY: Dr. Hassall and then Dr. Hudak.

DR. HASSALL: Just a question for my neonatology colleagues. Assuming that we really don't want to treat life threatening events with proton pump inhibitor or renitidine, and let me back up one step.

We do know that some children who have apneas or direct aspiration are dramatically improved by anti-reflux surgery. So I just wanted to ask you: in designing a study like this, how are you separating out those patients with apneas and bradycardias who may be having apnea and bradycardia due to prematuring, due to aspiration, and how do you in your clinical practices decide what tests to use or clinical appraisals to use in deciding how to send a patient in your unit for an anti-reflux operation?

In other words, what's the spectrum here? And how could you sort out those patients who might actually be benefitted by an operation rather than by an acid reducing drug?

DR. HUDAK: I guess I'll try to take that one. Actually in our unit it's very simple because surgeons won't do surgical anti-reflux procedures for children less than four kilograms, and those aren't the children we're talking about.

They're unwilling to do it. I don't know what your experience is, Lillian, but I mean, for all of the reasons that you went through in terms of the short-term efficacy of anisthen (phonetic) and the difficulty of doing it, surgeons I've worked with in the past ten years have sort of backed away from doing these procedures in children less than four kilos.

I guess I've been to harsh on my neonatologist colleagues. The implicit assumption is that children would come to be eligible for this study only after failing all of the other available therapies.

That is not the issue. Those are the kids that would present for entry into the study. So that should be fairly straightforward.

And generally what happens is these children come into a point somewhere between 32 to 35 weeks corrected gestational age, very close by any other criteria for going home, but still have predominantly two issues, and they usually go along together.

One is this bradycardia. I'm going to get away from apnea because apnea is very difficult to quantitate. The WR talks about obstructive apnea with a complicated system of measuring air flow at the nose or the mouth and usually an abdominal or chest wall sort of impedance indicator so that you can look to see whether or not you've got respiratory movements and airflow, and in point of fact, in a busy unit outside of, you know, units that are very accustomed to doing research protocols, there's so much artifact you could introduce for malplacement of these equipments that I'd like to get away from apnea.

So what we're looking at is bradycardia, which is clear, which can be, you know, captured on the monitor and analyzed, and desaturation or either of those things requiring some significant nursing intervention. I think those are clear.

But you know, the issue there is that they either have that or they've got, you know, feeding problems. I mean, they don't feed well, and you know, that may be a manifestation of reflux at least in some babies, too.

But those are the babies who present 32 to 35 weeks. They've got, you know, generally these two problems together, and I think the question is if you can document that these children do have acid reflux, which would be a short pH type probe assessment, you can debate how many hours you need on that.

I like the idea in this population a placebo controlled trial rather than a withdrawal, the more I think about it. I think it would be cleaner, and then you would know, you know. You could look at your endpoints 48 hours later and see whether you have efficacy and repeat a pH probe and see if there's any correlation with decreased acid secretion, decreased acidity, and improvement in symptoms on the medication.

So I really think we're getting to hung up about all of the difficulties of doing this trial. I think it would be, compared to other studies I've done, a relatively straightforward trial to do.


DR. JAMES: Dr. Hudak, what I think I hear you saying is that you would disagree with the inclusion criteria for the pneumogram that's currently in the written request. You're advocating more of an inclusion criteria that includes bradycardia and feeding difficulties.

DR. HUDAK: I think lots of babies have obstructive apnea that doesn't result in bradycardia desaturation, and I don't know what that means clinically.

I mean, if I were confronted with that data on a baby, I wouldn't know what to do with it. I go by bradycardias and desaturations and prolonged apnea that's, you know, greater than ten to 15 --

DR. JAMES: So the pneumogram is not a useful tool for you?

DR. HUDAK: I don't find the pneumogram useful.


DR. BLACKMON: Well, there are some standards, to just speak to the issue of the pneumogram. There are some standards that require not only the monitoring of respiratory effort in air flow, but also heart rate in making the diagnosis of obstructive apnea.

And I think whether that's the kind of apnea that you want to get into or whether you want to use the chime study extreme event documentation, which was, I think, probably a better standard for an apneic or an episode of instability that's concerning.

I'd like to go back to Dr. Hassall's comment or question about indications for doing fundiplication. I've worked with probably a dozen or more pediatric surgeons over the course of my time. A specific weight criteria was not usually an issue.

The indications for fundiplication surgery on a respiratory basis were clear documentation of failure of clinical improvement in a time when it should have occurred, usually manifested by recurrent aspiration episodes clinically ore recurrent appearance of infiltrates on X-ray that were in association with changes in the feeding pattern, usually increasing in volume feeds or bolus feeding.

Rarely did I ever have an infant that had fundiplication under two kilos in the absence of profound neurologic damage. Thus, those infants that were really profoundly damaged, and there was no way to advance enteral feeds without some mechanism of feeding in the stomach, did we ever go under two and a half kilos.

But the issue of when we went to fundiplication really was severe respiratory complications, by and large, in the absence of either esophageal abnormalities of an anatomical and functional nature or severe neurologic impairment.

DR. HUDAK: But that's your one to two babies a year.

DR. BLACKMON: That's correct.

CHAIRPERSON CHESNEY: Dr. Spielberg, and then I'd like to ask Dr. Murphy and Dr. Raczkowski where we go next.

Dr. Spielberg.

DR. SPIELBERG: I'm confused, which is not unusual with neonatal studies. I mean, we were involved in a study of a very different compound where we couldn't get two neonatologists in the same unit who attended month to month to agree how to feed the babies the same way.

I disagree that this is an easy study. I think this is a profoundly difficult study to do because I don't know what we're treating yet, and I don't really know the patient population and targets that we're looking at.

I've heard a lot about different kinds of babes with different kind of physiology, different maturational states. Working against us are two things: one, entry criteria and, second, duration of time because things are changing.

Apnea rates are changing with age, as are rates of GI function changing with age. So we have an outcome variable changing at the same time we have an input variable changing, all at the same time.

This is why in a sense I would be driven towards an enrichment design. Simply saying, you know, what is clinical practice right now like, in honesty, you try the drug. If you think it works, you keep the babe on the drug. If you think it doesn't work, you take the babe off the drug.

You know, a good clinician paying close attention to the patient by whatever criteria is going to behave that way. In a sense what this design does is say if we're going to do the study, we enter patients. Those who respond, we see if that response is really due to the drug in question by doing a withdrawal phase.

Having said that, I think the studies are going to be confounded by definition because of changes in maturation, changes in disease state, influence of the drug, that indeed we're working with irreversible inhibitors here, which is why the PK doesn't match the PD.

It's going to be a very, very difficult to assess study, which to me says I'm not sure yet that the study is ready for prime time. That is not to say we don't want to do it, and it's not to say that it's not important to get this information for the situation that Dr. Gorman described, you know, the happy spitters, where in honesty that's a practice issue.

You know, my second son, you know, was, again, an enormous laundry problem. He hasn't vomited in the past 14 years, but for that first nine months we used more detergent than was available in the City of Toronto to deal with the issue, but he grew and he was fine. So it didn't matter.

And I had a pact with the pediatrician not to intervene until nine months, and eight months, 30 days, and boom, it stopped.

We don't want drugs used that way, but doing studies is not regulating practice, and in a sense our common sense in practice guidelines should reflect that we shouldn't be using drugs as first choice for diseases that aren't diseases in the first place.

So that's not the issue. So I'm still concerned we're not quite there in terms of design. If I was responsible for designing the study based on everything I've heard today, I still don't know how I would do it, and I really wouldn't have confidence that I would answer the question, which is: do these drugs work in some children with apnea and bradycardia effectively?

And if I can't convince myself I can design that and really get the definitive answer, I'm not sure yet I should be doing it without some additional data, perhaps a good NIH study to provide the rationale and better definitions of the patient populations or better tools that we can use to make sure once we do the definitive study that it gives us a definitive answer.

CHAIRPERSON CHESNEY: Thank you very much.

You speak very eloquently for many of us who are still very much in a quandary, and when I think about my general pediatric attending, what are the patients where I really want an answer? It's those ones where we have tried everything and it still isn't working. Sometimes they came in with a life threatening event. Sometimes they are failures to thrive. Sometimes they are just repeated apnea and bradycardia.

And when we get to the point that our only alternative is reflux surgery, I would love to be able to look at PPIs in that population because of your experience. I think that's phenomenal if we could modify our surgical rate as dramatically as you said, even given that maybe it's not a very long lasting effect, but then maybe that's even more reason to see if these drugs work.

So, you know, when all is said and done, I can't really speak for the neonatologists, although I understand that population because we see some of them that aren't in the ICU.

But thank you. I think you really expressed the difficulty we're all having with this.

Dr. Hudak?

DR. HUDAK: I'd just like to make one comment, and that is that we deal with this all the time. The babies are changing maturationally in every organ system, and yet we've done good clinical trials in neonatology with objective results, clear endpoints, and so forth.

And I will still insist that this study can be done and be meaningful and be interpretable and give us an answer, not every answer, and it will probably spark more questions if we show efficacy, as to exactly what population that the drug is effective in and how can we better identify that population.

But I think as a first study, this can be done. If I took your reasoning to its extreme we wouldn't be able to do any study of any agent on any organ system, you know, because of all of the factors that you mentioned.

DR. SPIELBERG: Absolutely, but I think my greater fear is that we'll end up with a negative study that will perhaps end up disadvantaging kids who would, indeed, benefit from the drugs.

And we're dealing with a situation here where labeling does have an impact on that and where studies do have an impact.

I'm just saying we've got to work towards a study design that optimizes the chance of showing something if it is there, and I'm just not sure we're quite there yet with the endpoint as opposed to cardiovascular endpoints or other things which we --

CHAIRPERSON CHESNEY: Dr. Wilfond and then Dr. O'Fallon.

DR. WILFOND: This is a question for Dr. Spielberg.

You know, it sounds like what I hear you saying is that studies are needed, but you're making the distinction between the study that was done through this written request process versus through some other non-FDA related approaches.

And I'm not sure I understand the distinction between those two about when you pick one approach versus the other. So that's really sort of an open question for anybody, I guess.

DR. SPIELBERG: Well, just from an industry perspective, in terms of designing a trial, when we're doing a good clinical practice design trial with endpoints that, in fact, have been validated and tools that have been validated either by us or by external investigators, we have reasonable confidence that we're going to be able to present data to the agency that the review division is going to be able to look at, make sense of, and that everybody is going to be happy with.

There are many diseases for which we just don't understand enough yet how to evaluate that process. We're trying to do a study that has all of those implications for labeling and such. It would result in data that are really uninterpretable.

And those are often very hard judgment situations in pediatrics because now the beauty of what's happened in the last five years is that lots of drugs are being studied. The difficulty is that in the age before when so few drugs were being properly evaluated, you didn't have to worry about validated endpoints because there was nothing to study.

Now we truly have to worry about validated endpoints in order to do those studies, to get away from anecdotal medicine into evidence based medicine.

And the sad part is not only in this field, but in many other fields of pediatrics, we've been struggling because, in fact, when we look for those endpoints, they just aren't there, and it could take two, three, four years to get the endpoints so that we can actually do the study.


DR. O'FALLON: There are a number of things that concern me. One of them is that I think what I'm hearing is that there really haven't been studies done to get the information in this population. So patients are being treated within almost the lack of any information.

Any kind of information would be valuable, I think. So there is a philosophy of clinical trials, you know, the large, simple trial, but basically the idea is you enter the patient if the doc feels that the patient needs to be treated and wants to treat him.

You know, this would be done. We'd work i tout, but it seems to me that, you know, you could define if the doctor feels that the patient needs to be treated with this sort of thing. Then enter them in. The treatment would be given, and there would be the well defined failure escape criteria because, you know, if it's clearly not working, they don't have to go eight weeks.

But then there would be the randomization at eight weeks or six weeks or four weeks or whatever you guys thought would be the appropriate thing, and you could see whether it was the drug that was doing it or whether it was just something else.

But you would have a lot of information at the end. So if you found out that the ones that were always cured were, you know, the ones that turned six months or seven months or something during the course of the trial, you'd have some evidence that maybe it was maturation that was underlying and not the drug.

I think that doing a study like this would at least give useful information even if it wouldn't identify the best drug for any given condition.


DR. NELSON: I think we've sort of come full circle to the question as to whether or not any of these pulmonary manifestations or breathing manifestations, apnea, bradycardia, are pH related. And I was writing down four different study design choices, and we bounced back and forth between the assumptions about the role of pH.

So, for example, if it's an add-on to prove an effective therapy in nonresponders, you're excluding pH related disease, except for Bob's caveat about those who might not respond to renitidine. If you do it as a replacement for proven effective treatment and then a randomized withdrawal, you're assuming pH related disease.

If you do a standardized placebo controlled trial in nonresponders, you're assuming non-pH related disease.

And then if you bounce back to an active control equivalence trial, renitidine versus a PPI for apnea and bradycardia, you're assuming a pH related disease.

So it strikes me that until we sort out whether we think apnea and bradycardia are related to the gastric pH, it's not clear to me we have a study design that would make sense of those four choices.


DR. HASSALL: Yeah. I think that by suggesting, Dr. O'Fallon, that you should do these studies because there's information to be had you're a priori assuming that it is an acid related disorder. because we're using acid suppressing drugs.

I mean, I have a paper in front of me from Pediatrics, January 2002, "Gastroesophageal Reflux," just as an example of one piece of literature, and apnea of prematurity, no temporal relationship. Here they didn't even use pH studies or acid was not even a consideration. They used impedance, in other words, looking for bolus reflux.

So I think we're getting back to the question: is it the obligation of a study like this to prove cause and effect, or should we first know what causes it in order to even embark on a study in the first place?


DR. EBERT: Well, just briefly in response to Dr. Nelson, my other question would be whether it would be possible to do a three arm trial, one where you would have a placebo as well as an H2 blocker as compared to agents for the PPI. So that might address in some ways the issues that you talked about with regards to whether, in fact, this is an acid related disease.

DR. NELSON: Well, having the placebo arm in there would help you know if it's an acid related disease, but the presumption is if you believe it is an acid related disease, then having the placebo arm in there would be considered unethical.

So the honest answer is I don't know. I'd have to look at the evidence and decide. It's unclear to me. Is there any evidence that suggests that neonatal apnea, bradycardia if there is reflux is related to acid at all?

CHAIRPERSON CHESNEY: We don't have an immediate response. Let me turn to the FDA folk and provide us with some guidance.

DR. RACZKOWSKI: Okay. Well, I think we've had a good discussion on the Question 2. I don't think we're going to get to -- I'm sorry -- Question 3.

I don't think we're going to be able to get to Question 4. Unfortunately our clinical pharmacologist, Laura James, left because she had a flight to catch, but I wondered if anyone happened to have comments, including from the audience, about the pharmacokinetic and pharmacodynamic studies.

We did hear at the break from both Dr. Gardener and Dr. Kerns, and I'd be interested in pursuing Question No. 5 just very briefly.

Let me just say that the approach that the FDA took in children greater than a year of age is that enough is known about these acid related diseases in that age group that if you have a blood level of the proton pump inhibitor and you can match that in a child to the blood level in adults, that children and adults are not that dissimilar that you could anticipate that you would have similar pharmacodynamic effects in kids.

Part of it was a feasibility issue, that it's difficult to do pharmacodynamic studies in kids more than a year of age, and just in terms of doing a sample size.

But the underlying assumption now was that if you have blood levels, sure, there's no immediate correlation between PK and PD, and sure, we know that it takes time for these drugs to build up their pharmacodynamic effects, but if you can match exposure in an adult and in a child, then you would anticipate a similar pharmacodynamic effect in kids more than a year.

Kids less than a year, we were unsure, and so we asked for pharmacodynamic data.

CHAIRPERSON CHESNEY: Could I ask Dr. Kauffman? I'd be interested in his comments and then maybe Dr. Kerns would also be able to comment on this number five, specific PK/PD issues.

DR. KAUFFMAN: I think this is a PK/PD relationship that is different than what we most times deal with where we have a fairly direct relationship between what we're seeing in the plasma and what's happening in the effect chronologically.

This is an irreversible inhibitor, I guess. It's an irreversible inhibitor. So the effect last over a different time frame than what we see the compound's life in the plasma or measuring it.

What we would like to be doing is measuring it at the receptor, but next best is measuring the effect that we can measure in terms of acid production or acid concentration or hydrogen ion concentration in the stomach.

It seemed to me with this relationship that one approach would be to look, as Victor said, to look at exposure whether you define that as area under the curve in the plasma. that's probably the easiest way to do it. Look at exposure and try to approximate exposure in the child to what you have evidence for in the adult; that that measurement of exposure results in this 24-hour suppression of acid, and extrapolate that information, assuming it has essentially the same effect.

If we weren't completely comfortable with that, we could do a small group of children where we actually measure acid concentration over time and corroborate that our assumption is approximately correct.

And then we may want to do that -- I think the value of that is we're probably going to find that the -- and there was some hint of that this morning -- we're probably going to find that in the pre-pubescent group, the per kilo doses required to do this are going to be significantly higher than in the adult, the post pubescent individual.

So that we avoid the risk of under dosing and missing efficacy in that age group, and that could be done with a number of different ways, with traditional PK in a smaller number of kids or with pop. PK in a larger number of children, and that kind of information can be gleaned in the same protocol in conjunction with some safety, in the safety study.

One thing I've seen that I'm uncomfortable with is laying out a whole sequence of studies, one to do PK, one to do PK/PD, and another one to do safety and maybe efficacy in the population.

I think with a finite population of children to work with, we have to try to get as much information in a study as we can without overburdening it with doing too much in one protocol. But I think that one mistake that we tend to make is -- and I think I've seen it in some of these proposals -- is we have a protocol for every single type question we're trying to answer, and we're doing things in some of these samples of kids that we wouldn't need to do if we combined some of the protocols.

But I think in terms of PK, we ought to aim at exposure, looking for differences, gross age related differences. These are drugs that appear to have a very wide therapeutic range, a very large therapeutic index. So it's not like a drug that has a high toxicity or toxicity very close to the concentrations or exposures that you need for therapeutic effects. So we have some room to maneuver here.

CHAIRPERSON CHESNEY: Dr. Kerns is another PPRU representative.

DR. KERNS: I'll try not to make this sound like the Kansas City mafia.

Exposure response guidance I mentioned earlier hits right on the head with what Dr. Kauffman just said, and, Victor, you know, do these studies, have a role. Are they important?

I think it's very clear that if you look at the exposure there you see these drugs, and if you look at their ability to work in a single dose, there is an association there. It's clear now.

Now, what happens with multiple dosing with respect to the PD is not known. PK with multiple dosing is pretty boring because the drug is not there.

The difficulty with the PK/PD studies, and we've participated in a few of these, is that if you look at most of the PPIs, they are not pharmacologically clean substrates. These are polyfunctional substrates for cytochromes P450, 2C19, 3A4, which means when you look at the variability of the data, which was actually reflected in Dr. Hassall's J.Peds. paper when he reported the wide range of doses, what you really had there underneath it all was AUC had a huge range, a huge range, with the same milligram per kilo dose.

Now, if you go back to examining the impact of ontogeny on the pathways, you can't look at a benzodiazapine examine for 2C19, which was mentioned earlier, and make since out of omeprazole because a huge amount of it is biotransformed in the small intestine where it's also a P. glycoprotein substrate.

So a lot of what falls out in the relationships between PK and PD is the fact that there's so much variability. Now, let's try to separate age out of all of that. Let's try to get to ontogeny.

But we've first got to get to pharmacogenetics. How many studies of any of these drugs in pediatric patients have you seen include 2C19 genotyping or 2C19 phenotype assessment?

And the answer is in the public domain, zero. Now, that's important, especially if you're doing the study in San Francisco where you've got a huge percentage of Asians. Okay?

And I bring this up not to add controversy, not to put kerosene on the fire, but to say to sit around and talk about designs that ultimately have to get to exposure effect correlate, you have to be able to tease out the impact of age, and it has to be done effectively.

One of the limitations of pop. PK, even though it's part of the template, and I applaud that, population PK can be very useful as long as you've got a drug where the variability is small.

but when the variability is huge and you have no idea how to parameterize the model, you could wind up with, you know, kind of dog food at the end of the day and no answers that will really help children.

So these studies have to be designed very critically, carefully. They have to take into consideration the impact of growth and development on the disposition of the drug, and by all means, the exposure response stuff is critical because if the drugs work on the proton pump in a reliable way, in a reproducible way, make the exposure the same.

And as Dr. Kauffman mentioned, these drugs are not digoxin. You know, to give you an idea, omeprazole at a .4 milligram per kilo dose makes the same range of AUC, which is 240 to about 2,200 nanograms per mL per hour. Okay? Do you get the picture? Tenfold, one dose tenfold as the 30 milligram dose does in adults.

And the thing of it is when you look at the PD part, just as far as acid suppression, they both work the same.

CHAIRPERSON CHESNEY: Thank you for that great clarification.

Now we have to start doing genetics. Very, very, very interesting. Any other comments before we turn to our -- yes, Dr. Danford.

DR. DANFORD: I'm wondering particularly about the designs that involve pharmacokinetics in the under 44 weeks corrected gestational age population. If we've just spent the morning discovering that we have a poorly defined disease that we're treating and indications that are very murky, and we don't even know how to design the efficacy study to show whether it's good or whether it causes adverse effects, what are the ethics of exposing premature infants to these medicines to learn their pharmacokinetics?

CHAIRPERSON CHESNEY: I think that raises the whole issue of the immature GI tract, and there have in some animal models been associations with malignancy. So I think that's a very concerning issue also.

Dr. Murphy and -- no, I'm sorry. Dr. Kauffman.

DR. KAUFFMAN: This is not pharmacokinetics. I sit here watching us as we have for decades degenerate into research therapeutic nihilism because we can't figure out how to do it perfectly, and so by default, we're going to make the greatest ethical mistake, and that is to continue giving these medications to kids without any information, where we've been told by some people, particularly neonatologists, that there is a way to do this to at least get some information so that we're not completely in the dark.

Sometimes a candle is better than nothing, but it's not a spotlight, and it's a candle, and maybe we're striving for a candle here and that's the best we can do, but it's certainly better than being completely in the dark.

And I think too often we have allowed ourselves to by default end up doing the most unethical thing, and that is continuing to expose children to medications without the kind of evidence we should have.

We're all applauding evidence based medicine. It's hard to practice when there's no evidence.

CHAIRPERSON CHESNEY: What I think I've heard this morning is that, from the people who have been using these proton pump inhibitors now for years, is that what they need is the PK and PD data. That's what I thought I heard very clearly. So it seems to me like that's a given.

I think the area that we are least sure about is this association of respiratory manifestations with reflux that we do see in premature infants and in some term infants that ultimately come to reflux surgery. And I think that's for me where I'm not -- Dr. Spielberg is always much more eloquent than I -- but that's where I'm puzzled.

But the PK and PD data, it seems to me, we need, and I agree with you. To me it seems like that's a given. We should absolutely do that.

Dr. Santana.

DR. SANTANA: But I think the additional safeguard for that very young age group is that we do like, for example, we do with a lot of HIV trials. We try to get as much information to establish the relationships in the older populations first, and then once we clearly have identified those relationships, then we start exploring them in the much younger age groups to try to minimize the risk and safeguard them.

So it's not you do it. It's the timing of when you do it, I think, with good information to minimize that group.

So it needs to be done in that group because Ralph is correct. If not, we're not going to learn that, but we minimize it by getting the information on the older age groups first.

DR. DANFORD: I don't disagree with anything that Dr. Kauffman or you just said. I raise the question of whether people like Dr. Nelson are going to let us do this.


CHAIRPERSON CHESNEY: Dr. Raczkowski and Dr. Murphy.

DR. MURPHY: I mean, one extreme, which I don't think anyone wants here, is that we don't have enough information to really understand as fully as we all would like as scientists and physicians, and therefore, you know, the agency should just not issue anymore written requests and wait until NIH funds the studies and we all have precise understanding of what might be the best endpoint.

And I think that clearly is not what we want to do. We have always said that we understand for all of the reasons that have been stated that our knowledge base is not what we wish it to be, but it's our responsibility to try to improve that knowledge base.

And then we want to do it in the most ethical and most hopefully enriching way as far as information is concerned.

Clearly, this is a difficult area, and I said in the beginning we brought this to the committee because we feel that what we have asked for in the past, we've learned that we think we have more questions. That's exactly what happens, is that as you move forward and begin to study children, you actually have more questions.

And we think that we need to develop in the older age group the better dosing information and better relationships between the dosing and the outcomes.

I think that for the older population the committee appears to agree with us in that area. I think that the issue here that we're all struggling with and we've heard both sides of this argument, which is that we don't even know enough to design the trial or that the people, the neonatologists feel that they do know enough to at least give us their best assessment of what the endpoints should be.

And where we're really struggling is because of that limitation in our knowledge of what the best endpoint may be is what is the best trial design in how to define moving forward with getting information whether there is this relationship or not.

And I think one of the things that we may need to consider here is as we go forward in the older age groups with potential PK/PD studies, would be instead of waiting completely is to ask is there -- and we've done this. In some ways this is what PK/PD is, one could say, but it wouldn't really be. It would be more of the outcome type of study -- would be can we define maybe a test of our hypothesis in this young age group, that the trial should be a test of whether we have the right endpoints or not instead of going for the complete question of efficacy.

I think that might be something that we have not really considered as extensively as we may need to at this point.

Another question that was put to me by medical officers during our discussion would be if we said for the younger age group -- and I'm going to just not even put a date, age on its right now -- somewhere below six months down to a weight that one can keep alive, if you will, in the preemie; if we don't do an efficacy trial, what are the most important questions that the neonatologists would want us to try to address?

I think that that might help us work on this some more, think about it some more. So I Don't know if we actually have time to go around to ask that, but since Bob isn't there, how many neonatologists or others do we have? If we could ask you to think about that and provide us some input on that.

CHAIRPERSON CHESNEY: Well, we have at least two neonatologists and Dr. Spielberg.

DR. SPIELBERG: Let me try to take a quick crack at it because I think what Ralph said is the heart of what we're all here about, which is to shed maximum light in often very, very difficult situations.

There's no question but that one of the issues in the preemie is formulation. You know, these compounds by definition have all kinds of problems. We talked at the break about even in nursing homes of crushing omeprazole and putting them down G tubes so that no one gets efficacy.

So we need a formulation that works, and in that context, we need good PK on that formulation, and we need good PK/PD on that formulation so that if, indeed, we are going after an acid suppression mechanism, neonatologists are going to know how to do it because that's the first key thing that we want to understand here.

Can we suppress acid appropriately, safety? What are the doses? And how do we administer it accurately in the volumes required for these small babes so that they, in fact, receive the drug in an appropriate way, recognizing that GI absorption, all sorts of things may differ here, and we've got to get that part of the story down for sure.

If we went ahead, regardless of what kinds of efficacy studies, be it carefully done PK outcome studies done by NIH by the Neonatal Network or whether it be sponsored studies, we need the formulation, the PK and the PD, before we even start off so that we know that those trials will have optimum control of acid if the question is: is acid suppression going to lead to the outcome of concern?

So those things I think we for sure need, and are very reasonable to do. Then the question is the efficacy trials and are they ready for prime time. Do we need more now?

In my heart of hearts, just looking at what I would try to design, I think we do need more because, again, I mean, the thing I'm most fearful of is doing a study that's negative because we've really picked -- and we'll never get to do it again. I mean, you know, we're not going to be able to do it or --

DR. MURPHY: Steve, I don't agree with that. You know, maybe -- maybe --

DR. SPIELBERG: Well, I am concerned because --

DR. MURPHY: Bob can kick in here, but I mean, we do negative studies. We get negative studies, and we go on and do more studies because we know that one negative study does not constitute the answer all the time, and some time in that negative study we actually learn quite a bit about how we need to do the next study better or what we shouldn't do in the next study.


DR. MURPHY: So I don't want people to leave the meeting saying because we have one negative study that we'll never do another study.

DR. SPIELBERG: But in peds. it is all the more critical because of patient numbers and because of other interventions.

DR. MURPHY: But particularly if you have efficacy.

DR. SPIELBERG: We're beginning to chew up the number of neonates with different drugs that we're going to be studying. So we do have to be careful.

It's not to say we shouldn't do it. I'm just putting out the cautionary note that I'm not sure how I would design the study now. Maybe some additional data really would provide us the basis for doing it, but regardless, formulation, PK, PD, that's going to be the basis of any of the studies.

CHAIRPERSON CHESNEY: Dr. Blackmon and Dr. Hudak, you've been on the hot seat all morning. Responses to Dr. Murphy?

DR. BLACKMON: I don't know that I have a good answer for her in terms of what we need beyond what he's already outlined. A background study, and I'm not sure that this particular step in it is really the issue as does acid reflux have a significant etiology role in apnea and bradycardia that is of serious nature.

Let me say right off the bat I do not think it is a part of apnea prematurity, which is a mandatory drive, maturational problem. It has nothing to do with that.

I do believe that a study could be designed to answer that question and measure efficacy. It would require a very large, multi-center population to do it because I think the numbers of infants in which that is the probable etiology are relatively small in an already small population of very premature infants.


DR. HUDAK: Well, I would just echo Lillian's comments. I think that, I guess, to give some idea of the number of patients that might be eligible with the criteria that we sort of loosely talked about, my nursery that has about 600 -- two nurseries that have about 600 admissions a year a piece; we probably have about two to three babies a month to be eligible in centers that large.

So the need for a good, multi-center study is clear, and I think, you know, the formulation PK/PD data are critical.

I would also want to very carefully look at the known adult toxicities and just make sure that we look at those matters in the babies that are dosed, you know, whether they're related to possible hepatic issues or whatever, but just to design it where we look at some sort of a chemical safety profile while we're at it, if that's relevant.

DR. RACZKOWSKI: I want to thank the committee for all of their considered discussion. It's been extremely helpful, and we've held you back from lunch, but it's been very, very helpful to the agency, and on behalf of FDA, I want to thank everyone, including the invited guests.

CHAIRPERSON CHESNEY: Could I suggest that we reconvene at quarter after two? That would be an hour.

And I would also like to thank everybody who made comments today. I think this has been extremely interesting, and everybody here added yet another piece to this puzzle. Thank you all very much.

(Whereupon, at 1:07 p.m., the meeting was recessed for lunch, to reconvene at 2:15 p.m., the same day.)
















(2:21 p.m.)

CHAIRPERSON CHESNEY: I'd like to start with a few administration issues.

Dinner is on our own tonight. Use your salary that you got today for dinner tonight.


CHAIRPERSON CHESNEY: Tomorrow morning's meeting starts at nine o'clock, and if we could all meeting in the lobby at 8:30, we'll arrange to have taxis there so we can take group taxis to the FDA.

Be sure to check out of the hotel in the morning and have your luggage to take with us, and --

DR. SPIELBERG: Joan, for those of us not staying here, what time are the taxis going to leave the hotel?

CHAIRPERSON CHESNEY: We're ordering them for 8:30, and I guess we'll probably need more than just enough for bodies because of luggage maybe.

The training will end at two o'clock tomorrow afternoon for those of you with or without plane reservations that can be modified.

And one other announcement. Dr. John Walkup from Johns Hopkins is part of our group today, and he can hear us and we can hear him when he speaks, but otherwise, we won't know that he's there; is that correct?

DR. WALKUP: Yes, that's correct.



Tom Perez was just telling me I should ask you to say something, and I hadn't quite made it that far.

So this afternoon we have a very interesting collection of issues to address, and I guess -- I don't know, Dr. Murphy, if you want to make introductory comments or Dr. Roberts, or should we go right away to Dr. Willoughby?

DR. WILLOUGHBY: Okay. Thank you, Dr. Chesney.

I'm Anne Willoughby. I'm the Director of the Center for Research for Mothers and Children at the National Institute of Child Health and Human Development at the NIH.

And it's a pleasure for me to join my FDA colleagues today in discussing some important issues with the distinguished Advisory Subcommittee.

As you all probably know, it's stated in the Best Pharmaceuticals for Children Act that not later than one year after the date of enactment of this Act, the Secretary, acting through the Director of NIH and in consultation with the Commissioner of FDA and experts in pediatric research shall develop, prioritize, and publish an annual list of approved drugs for which there is no patent protection or market exclusivity.

The act goes on to state that in developing and prioritizing the list, the Secretary shall consider for each drug on the list the availability of information about its safe and effective use, whether new information is needed, whether new pediatric studies concerning the drug may produce health benefits in the pediatric population, and whether reformulation of the drug is necessary.

So we're talking about the generation of lists here. What list or lists are we talking about?

From an implementation point of view, there are two. That is, there's a preliminary priority list that contains a number of drugs that are slated for consideration and evaluation starting in fiscal year 2002.

My FDA colleagues, Dr. Rosemary Roberts and Dr. William Rodriguez, will present the considerable work that permitted the development of the preliminary priority list of drugs.

After their presentation, I'll briefly summarize the role of NIH in the further refinement of this 2002 preliminary priority list.

I'd like to underscore the fact that the preliminary prioritization list by FY 2002 is intended to accelerate the implementation of the BPCA. So we're talking about a list that's already here and we're going to present today.

The other lists refer to the new annual list that shall be published in 2003, 2004, 2005, and 2006 of drugs prioritized for study in pediatric populations.

The process for the generation of these annual lists that will follow the list we'll present today for 2002 will insure that the periodic examination of new knowledge and the identification of new needs with respect to drugs for use in the pediatric population will occur regularly.

At present, the process for the generation of these annual lists has not been specified.

It's my pleasure right now to turn to Dr. Rosemary Roberts who's going to present the considerable background that permitted the generation of this list.

DR. ROBERTS: Good afternoon and thank you all for being here and thank you, Dr. Walkup, for teleconning in.

And I wanted to just talk to you about yet another list. You know how much we loved the last list. Well, if you don't, you will know as I get through this talk.

Next slide.

So I'm going to go through the various lists that we've had to date and then end with the off-patent list, which is our charge here today to talk about a process for developing that list and prioritizing it.


Now, the first list was actually started to be worked on in 1995, and that was by a working group of the initial pediatric subcommittee that was formed in December of 1994, and in your packet you will see this two-pager, and all it does is it just talks about how this list was developed.

And the charge of this working group was to identify drugs that are most widely used in pediatrics on an out-patient basis for which there was inadequate use information.

And some of the general findings they had were that in the population less than two years old, there was almost no drug that had any pediatric use information.

And for drugs that were used a lot in pediatrics for classes, categories such as for asthma, seasonal and perennial rhinitis, which are very commonly used in children, there was almost no information; whereas for the anti-infectives, there did tend to be information that was collected by sponsors, mainly because of one of the bread and butter general diagnoses of the general pediatrician is otitis media. So there was always interest in developing antimicrobials for otitis media.

Now, the ten drugs that were on this list, and some are still on the list, were albuterol inhalation solution, and at the time this was put together, there was information on how to use this product down to the age of 12.

Subsequently, information has been -- this has been studied. Albuterol solution has been studied, and we currently have labeling down to the age of two.

Promethazine hydrochloride has not been studied.

And ampicillin sodium, this was a parenteral use, and remember this is out-patient data. This is from IMS, which is an international marketing survey company, and they have 2,900-plus physicians where they actually go into the offices and look at mentions of the drugs, and this was parenteral use of ampicillin. It has also not been studied.

Auralgan otic solution for ear pain also has not been studied.

Clotrimazole betamethazone diproprionate. Actually the entire betamethazone diproprionate topical formulations have been studied, including the combination product with clotrimazole under the -- via written request, and that product is now currently labeled all the way down to birth.

Fluoxetine hydrochloride, or Prozac, has been studied. It's been granted exclusivity. We do not have labeling to date.

Now, cromolyn sodium, we do have a cromolyn sodium that's been studied, but it was a nasal spray that was studied for allergic rhinitis, and as an over-the-counter indication. What was referred to in this initial list was Ental or chromalin sodium for asthma.

Sertraline hydrochloride, or Zoloft, has been issued a written request, and those studies are underway, and may even come in. I'm not sure.

Methylphenidate hydrochloride, or Ritalin, it was asking for studies below the age of six. It has not been studied to date via written request. WE have not issued a written request, and the reason is we really did not know how to study attention deficit under the age of six years. How does one consistently diagnose it? What criteria to use; what kind of tools for assessment.

The National Institutes of Mental Health currently has an ongoing trial looking at exactly that in the less than one year old.

Metaproteranol sulfaterol, Alupent, has not been studied to date. Information was needed on the less than six year old.

And beclomethasone diproprionate nasal sprays, written request was issued, but the studies were never performed.

So that's the first list.


Now, I'm going to talk about the FDAMA list, and I want to highlight some things, and Willoughby just read to you what the Best Pharmaceuticals for Children Act says as to the list that was to be developed under the new act, and this comes directly from the Modernization Act.

Not later than 180 days after the date of enactment, which was 11/21/97, of the Modernization Act, the Secretary, after consultation with experts in pediatric research, shall develop, prioritize, and publish an initial list of approved drugs for which additional pediatric information may produce health benefits in the pediatric population, and the list is to be annually updated.

Now, there are several areas of similarity in what we were charged to do by the Modernization Act. It was delegated to the Secretary, who delegated it to us. It was the Food and Drug Administration Modernization Act.

We were to consult experts in pediatric research as we are to do for the Best Pharmaceuticals for Children Act list. We were to develop, prioritize, and publish an initial list within 180 days.

We now have twice that amount of time to do it, and it was to be a list of approved drugs only. It doesn't say anything about the status with respect to exclusivity or patent protection, and it was to be information that may produce health benefits in the pediatric population.


Now, the initial working list, we actually consulted many, many organizations and groups and got their recommendations: the American Academy of Pediatrics, PHARMA, the National Institutes of Health, the Pediatric Pharmacology Research Units, the National Pharmaceutical Alliance, the Generic Pharmaceutical Industry Association, National Association of Pharmaceutical Manufacturers, and the U.S. Pharmacopeia.

In addition, any drug in the orange book that had existing patent protection or exclusivity was put on the initial working list.


Then this working list internally, we divided all of these drugs that were now on this list, and it was several hundred. We determined which divisions regulated each product, and we then put that on a list with the indications that were approved in the adult, and asked each of the regulatory divisions to look at the drugs on there and to see if they fit one of three criteria.

And really the first criteria is sort of like the definition we use for a priority review of a drug. Will it have a significant improvement compared to marketed products labeled?

Well, marketed products labeled, remember I just said most drugs weren't labeled. So it was not a problem here to be concerned about whether we had too many already in this category labeled.

"For use in the treatment diagnosis or prevention of the disease in the relevant pediatric population", so that was one criteria, or it was being widely used in the pediatric population.

For those of you that were here this morning, we know there's a lot of use of the proton pump inhibitors in the neonate, in the less than one year old, and that's part of the reason that's driving trying to study it, because it is being used.

And it was defined for purposes of this criterion as at least 50,000 prescription mentions per year. Now, that dates back to the mentions we talked about in the IMS database, or it could be a class of drugs or an indication for which additional therapeutic or diagnostic options were needed in the pediatric population.

If a drug, according to the division that reviewed it, met any one of those three criterion, it was put on the draft list.


The draft list was published March 16th of 1998 in the Federal Register. So we actually got that out within four months of when the Act went into effect, and we asked for comments to come back within 30 days that we then had to review because we had to publish that list by May 20th of 1998.


There were 89 comments that were received. Many of them simply asked that a specific drug be added to that list or deleted from that list for whatever reason the commenter had.

There were several that said the criteria that we used were far too narrow, and there were several that said one should include all drugs used in the treatment of diseases or conditions that occur in the pediatric population.


So what we decided to do after we reviewed those comments was to say that any drug that's approved for use in adults that's applicable to the pediatric population is on the list. That's a lot of drugs.

Now we had a challenge. That's the list. How do we prioritize this?

Well, depending upon which group you talk to, whatever drugs they need to treat their condition are the drugs that go on the list first, without a doubt. But that wasn't helpful to us.

So next.

What we decided to do was that if you fit one of the three previously outlined criteria, you became part of the priority section of the list, and so we published this list May 20th of 1998. It was a bit large and unwieldy to deal with, as it had 400 to 500 drugs on it. And we updated it manually as we were mandated to do every May.

And that meant we removed drugs that were studied or had been labeled. We added approved new drugs that were for conditions in adults that were applicable to children. Also, industry could petition the agency to put a drug on, and we looked at those petitions, and if the petition was granted, we added that drug for the indications that they petitioned to go on with.

And then the division had a chance to relook at all of their drugs that they regulated to see if they had other input that had come in over the past year, if they had reasons to take it off because of some safety concern that had developed, et cetera.

So it was not an easy task to update this every year. It took an awful lot of resources by the agency to do this.

So what if you were on the priority section of the list? What did that do for you?

Well, it didn't constitute a written request. So we still had to write a written request if you were on the list.

It didn't mean that you would quality for pediatric exclusivity, and there could be several reasons. One, you may not do the studies that were asked for in the written request.

Two, it may have been for a product, like an old antibiotic, that didn't have any exclusivity or patent protection to which pediatric exclusivity could be attached.

And the sponsor wasn't required to do the studies in the written request. So what exactly it did to be on the priority list is questionable. So it didn't help us in prioritizing, we learned, because we couldn't get a consensus.

So we ended up with a long list that was unwieldy. It's a voluntary program. So why prioritize the drugs that need to be studied when you're going to issue the written request, and if industry is interested in doing it, they'll do it, and if they're interested in doing it, they'll also send you a proposal and indicate to you they want to do it as we've now received over 300 proposals since June of 1998.

It was resource intensive for us to update this list, and while we're updating the list, we're taking the same people that are supposed to be reviewing the proposals, reviewing the supplements, and now we've got them updating the list.

So overall the list wasn't helpful from our point of view, and actually in the report to Congress that we were mandated to write and that we submitted to Congress in January 2001, we recommended eliminate the requirements for the list.


Then at our request, we asked the American Academy of Pediatrics for their suggestions of drugs that are most frequently used by pediatricians in the care of their patients and for which additional information is needed.

And Dr. Rodriguez will talk to you about that list and how it has subsequently been used in putting together the preliminary priority list.


Other lists historically, the USP has looked at available information, pediatric information for products that are used off label in the pediatric population, and post enactment of the Best Pharmaceuticals for Children Act, the USP has put together a list of off-patent and off-label drugs that have narrow therapeutic indices or for life threatening diseases and are being used in the pediatric population.


Now, we have the Best Pharmaceuticals for Children Act, and what I can say is that Congress did listen to us. They did read our report, and they did some of the things that we asked.

They eliminated the list. However, in the next section they created a new list.


DR. ROBERTS: And this is a list to study off patent. So in order to be on this list, and the criteria that are outlined in Section 3 of the act, most of those criteria refer to the fact that you have to be off patent and have no exclusivity remaining. So you have to have an approved generic application or have submitted one and qualify to get a generic application.

So we are now mandated to do a new list. Now, they created a research fund. They authorized appropriations of $200 million for FY 2002 so we could do these studies, but we got this much in the budget to do them. So we got a research fund authorized, but not money yet.

Okay. Next.

Now, this is what Anne just read to you, and now we have a year after the enactment, which was January 4th, 2002, and now NIH is in the lead. They're to consult with the FDA and experts in pediatric research, one of the reasons that we're here today, and to develop, prioritize, and publish an annual list of approved drugs for which -- next -- now, the drugs on this list I want to emphasize are to have no patent protection or market exclusivity. That is, they are not listed in the orange book, and they need additional studies to assess the safety and effectiveness of the use of the drug in the relevant pediatric population.


Now, in developing and prioritizing this list, we are to consider for each of the drugs availability of information concerning the safe and effective use in the pediatric population whether additional information is necessary, whether new studies concerning the drug may produce health benefits in the pediatric population.

Now, I want to remind you this is exactly the same charge as we had under the Modernization Act. We are to assess whether the drug, if studied, may produce health benefits in the pediatric population, and whether reformulation of the product would be necessary to study it in the pediatric population.


Okay. Now, other things that are outlined in Section 3 is the pediatric study that is to be done on these off-patent drugs, and it directs as to how this process is to be completed.

FDA, in consultation with NIH, is to remain in the driver's seat and write the written requests for these off patent drugs, and once the written request is written, we are then to issue it to not only the innovator, if there's still an innovator in the market, but to all approved drug holders of that drug.

And they then, within 60 days, are to let us know whether they agree to do the studies that are outlined in the written request. So they get 30 days for the first right of refusal. If none of the holders of the approved applications agree to do the studies, then it will get referred over to NIH, and those holders of the approved application have no right then to bid for the contract.

NIH, in consultation with FDA, shall publish a request for contract proposals to conduct the pediatric studies that are described in the written request.

So thank you very much. Dr. Bill Rodriguez, Director of Science in the office, is going to talk to you about how we put together this preliminary list.

DR. RODRIGUEZ: Thank you.

It's interesting that one list led to the other, and what you're going to be hearing about very soon is the hybrid culmination of lists.

Next slide, please.

Giving equal time to everybody was very important to demonstrate that not only do we produce them from within, but we also get some of the information from our resources that are in the community.

And essentially in July of 1999, Dr. Robert Ward, who was chairing the Committee on Drugs of the American Academy of Pediatrics, provided a list back to the FDA, a list which actually had now information from current use by pediatricians. Essentially it had information in terms of ranking which actually have been provided after written and oral requests from the committees, the sections, and also from publications in the American Academy of Pediatric News of general pediatricians in the community.

So essentially that information was provided, and there were three categories, priorities that were ranked in the list, and essentially what I did was, if I could have the next slide, please, was first of all to alert you that these were patent and off-patent drugs together, and remember our current mandate is to look at the off-patent drugs.

There were 281 drugs that were ranked, and we concentrated on looking at the 126 drugs in priority number one or the highest priority.

It's interesting to keep in mind that that, again, is a combination of patent and off-patent drugs, which was exactly the way that the FDA priority lists of '98, '99, 2000, 2001 was composed. You had patent and off-patent drugs in there, too, usually to a ratio of three to four to one.

Next one, please.

We also used other forces, and as you heard Dr. Roberts speak to you earlier, we used some of the IMS data and also that essentially listed a number of the top ten drugs, and it's interesting again that of those listed in '94, some of them had actually now been labeled, and number two, some of them had received written requests.

So some progress was going on, but there were still four in there that did not have a written request, didn't have any labeling in pediatrics, and again, were listed as very high in terms of use.

Could I have the next slide, please?

So this thing which may not be very readable, but which was provided to you all in your pre-meeting package and it's available again in a more completed version in Dr. Murphy's handout essentially took a look at the top drugs that were listed, including the ones that were in terms of use and not in the FDA list.

It included also information that had what's available. As you can see, there are age groups in which pediatric information is needed essentially from our 2,000 lists of drugs and essentially addressed the divisions in there that were responsible for the specific drugs.

As you can see, some of them were not in the FDA priority list, and you can see the check mark next to it.

Next slide, please.

So now we have sort of a, quote, unquote, priority list that is provided to the divisions for input. So essentially they would be able to tell us, "Wait a second, you know. This information is missing, and therefore, this should not be used," or, "we should add this or we should subtract this," so essentially trying to capture as much of the information as we could since we were moving forward in this process.

And we ended up with a preliminary priority list that, quote, unquote, is listed in there that included prior Academy of Pediatric lists, the FDA updates in these divisions, and some of the information from the IMS and Children's Hospital Corporation of America data.

So this is now updated to 2001, and Dr. Murphy will be going into this further on when she speaks to you all.

So the third thing that we did -- I mean, the other thing that we did is in the next slide. We provided this preliminary priority list to members of an ad hoc expert panel of the NIHCHD, which represented individuals with, well, recognized expertise of various walks in the pediatric field, and they were to look at it, and Dr. Willoughby will be actually going over the next iteration. As you can see, it's a work in progress, and it will continue to be in progress for a while.

Thank you.

DR. WILLOUGHBY: I think one of the things that is absolutely clear is the list that we're going to talk about today stands on the shoulders of innumerable individuals who have been doing a lot of work in this area for many years.

So NICHD took the list of 19 drugs that Dr. Rodriguez has just told you about, and we convened a panel of experts in pediatric pharmacology and people expert in the use of drugs in pediatric populations in April of 2002.

These experts included Dr. Ralph Kauffman, Dr. Richard Gorman, Dr. Lillian Blackmon, Dr Robert Ward, Dr. Philip Walsen (phonetic), and Dr. Wayne Snodgrass.

The federal staff present during the consideration by these experts of the list of 19 included Dr. Dwayne Alexander, who is the Director of the National Institute of Child Health and Human Development; Dr. George G. Akoya (phonetic); Dr. Gilman Grave; and Dr. Bill Rodriguez from the FDA. And, of course, several of the people I've just mentioned are present today.

The group was briefed about much of the information that you've just heard, and they were told that the purpose of the meeting was to review and analyze this preliminary list of 19 drugs and then also to identify other drugs that merited additional study in pediatric populations in their opinion.

It was emphasized that the prioritization should be objective and evidence based, and that the needs of children in different age groups and subpopulations should be considered.

Dr. Kauffman chaired the meeting and led the group discussion. He began by stating that the PIs, at the Pediatric Pharmacology Research Units had in 1999 reviewed off-patent drugs in need of study, and that they had considered most of the drugs on this list of 19, and there were four in addition which they believed merited consideration: ketamine, amphotericin B, bumetamide, and morphine.

Dr. Richard Gorman commented that nonionic contrast agents had not been studied in pediatric populations, and then the group also mentioned that methotrexate, because of its prominent role in the treatment of autoimmune diseases ought to be considered.

The group also agreed that they wished to consider diazoxid in the treatment of hypoglycemia be included on the list.

So after considerable discussion, and I have the record of those discussions, if the committee would like it entered into the written record of this meeting, the experts were asked to individually, after discussion with each other, but not in consultation with each other, to privately prioritize the group of drugs from the list of 19 and also from the drugs which had been added to the list early in the discussion, that is, the four drugs recommended by the PPRU, the nonionic contrast agents, methotrexate, and diazoxide for the treatment of hypoglycemia.

The individuals at that meeting voted separately, and what emerged was what we have chosen to call the highest priority cluster, and then the next highest priority cluster.

In the highest priority cluster are dopamine, lorazepam, doputamine, morphine, acyclovir and ketamine.

The next highest cluster includes nonionic contrast media, amphotericin B, nitroprusside, and valproate.

The remainder of the drugs are arrayed on a lower priority list after that.

Now, the reason we are considering these to be a cluster is it isn't possible or reasonable to say, "Here's drug number one. Get it off the blocks. Here's drug number two. Get it off the blocks."

Rather we have this cluster which were are going to partner with the FDA in working on through the process that Bill and Rosemary have described in order to see that studies are initiated on these drugs in pediatric populations.

And so that essentially is our working preliminary list. Now, you might say, "Well, why rush to a list in this fashion?" although if you consider the background of it, it maybe is not as much of a rush, and that's because the secretary has committed to obligating funds in FY 2002, which ends at the end of September to study drugs on this list.

So there's a lot of process even with this preliminary list that needs to be gone through involving the written request and potentially the generation of RFPs.

So that was the process that brought the 2002 cluster of prioritized drugs to the table today.


DR. MURPHY: What we are going to do is to try to talk a little bit about criteria that we have been using and ask you for your assessment of should we continue to use these criteria, should we expand these criteria, and any other comments you wish to provide us on how to move forward both in development of criteria and the process because those are the focus of the two questions really that we have for you today.

Next slide.

I am also going to talk a little bit about this set of 19 not because we want you to design trials for us -- no -- after this morning, but because we really want you to look at what's going on in the way the clusters look when you begin to apply these criteria of use and impact by definition of where we think the gaps are to that 19 so that you can see how it's beginning to play out when you address our questions that we're asking you.

Next slide, please.

One thing i did want to emphasize, and Rosemary did a good job of doing this, is that we have had a number of definitions under which we have been working as to how we decide what the benefit would be. One is the meaningful therapeutic definition which is under the rule, pediatric rule, and that definition is a significant improvement in the treatment diagnosis or prevention of a disease compared to marketed products adequately labeled for that use in the relevant pediatric population versus the definition under which we have been working for FDAMA and are working in the present in the best -- I misspoke this morning and said "better." Forgive me. It's the Best Pharmaceuticals Children's Act.

So we do have this definition, "produce health benefits," and what we're asking you is beyond looking at the numbers of use and the missing -- identifying the gaps, are there any other criteria that we ought to be thinking about as we move forward in trying to define what is producing a health benefit.

These are some additional factors one might consider, and we would ask you to think about these and to address some of these as you answer our questions.

Certainly you've heard the need for additional options. that's important. That would be a positive factor in why one would develop a written request or wish to have studies conducted in children.

You need either a therapy studied or additional therapy studies in serious and life threatening disease, and in pediatrics we have many orphan populations. Not only is all pediatrics considered an orphan population, but certainly the neonate is another subpopulation, nd certainly rare diseases within the pediatric population continues to be such populations.

Negatives from our perceptive, the "me, toos." Do we really need a 15th cephalosporin study in children? Some would argue yes, but that is something I think that what is the definition of enough?

I hear somebody say this morning after we have one we shouldn't issue anymore. I think you would get quite an argument on that, that patients can't all tolerate the same product and that's why we do need options.

A product may have a higher adverse event or a rose adverse event profile, but if it's the only other option, maybe we do still need to move forward in asking for studies for that product.

A narrow therapeutic index when alternatives are available might be considered a negative reason or a reason not to issue a written request.

Next please.

So our criteria to you, and we're going to stand down here in a minute and ask you to address these. The questions are: for the criteria that we should use in thinking about developing these lists, should our volume, how often these products are used in children -- again, we've heard many products are used quite a lot without ever being studied. How important is that criteria?

It is mentioned in our rule. It's mentioned in a number of places as being something we should evaluate.

The impact. I've indicated that the impact definition right now is produce health benefit. So how do you really define impact?

Are these two criteria adequate for selection of drugs for the list to be studied, parts to be studied that are off patent?

And if yes, if that's sufficient, those two alone, would you help us with the definition of produce a health benefit? Any other thoughts about how we might define that?

And if not, why not? What other additional factors would you consider? Just some of those that I put up on the slide, if you would.

Second would be process. Anne and Dr. Roberts and Rodriguez and Willoughby have described a process here. What do you think about that process? We'd like to have your thoughts about are there other sources the FDA and NIH should consider in the development of the list.

And is there any weighting to this process, if one wants to get really precise about it or not?


The priority list must be produced by January 4th, 2003. What are the committee's recommendations for facilitating timely input into the development?

You've heard about how extensive input has been sought in the past. You've heard about you can get ten different groups in this room and depending on the disease of the group that's representing you will get ten different lists.

We do clearly seek input, but we also need to have input in a timely and effective manner that allows us to move forward so that we can have products on this list that get studied. So we wish you to balance that in your consideration today about what process do you think would facilitate input of this committee into development of a list.

And in addition to that process for this committee's input also, how would you like to have your updates, if you will? What do you want to hear about? How much detail you want to hear about the studies that were conducted.

Certainly I would think you would want to hear about what labeling has been resulting or not resulting, but we'd like to hear what is of interest to you in feedback on an annual basis.

Now, I am not going to ask for discussion on the 19 items that we're going to -- well, actually 18 because I left auralgan off. I'm going to go through them very quickly, and we don't seem to have a pointer.

So I wanted to just to through with you -- does somebody have a pointer? No? -- what these products look like when we applied use data from the children's health center database that has been newly developed. I want to please lay out the caveats about this database.

These are absolute numbers. They have no projection methodology associated with them, unlike the IMS data. So what I'm telling you is the numbers that you see under the CHC data reflect literal absolute numbers for 25 -- is it 25 or 29, Rosemary? I think it's 25 hospitals that range from free-standing children's hospitals to hospitals within larger complexes, and it's from their pharmacies basically.

So those are absolute numbers without projection methodology applied to them, while the IMS data is data that is mentioned and has some projection methodology associated with it.

Thank you very much.

So we have for cardiorenal these five products that have been identified as needing further study in children. You can see that within those 25 children's hospitals diazoxide is not used very frequently compared to dopamine. I think that's a level of comparison that you can use this data. That's about all you can do, is just look within the data to compare high use to low use at this point.

We also don't have any IMS data on this. Remember IMS is out-patient. It's one of the reasons we have worked for two years now piloting what mix of hospitals we need to try to get sensible data on pediatric in-patient use, because some of the databases we're using were really adult based databases, and when we saw that they had no use of albuterol in the various pediatric age groups, we knew we had a problem.

So this database was developed, again, to focus on in-patient databases of pediatric hospitals.

And the missing information that's been identified is really from birth to 16 years for all of these for use in hypertension, hypertensive crisis or for digoxin for very specific arrhythmias.

We handed out to you just so you would have it to compare as you think about this the actual indication associated with each one of these products, whether it has any pediatric information at all, which included a comment in the pediatric subsection or the dosing section.

And we have a new medical author, Suzanne Olness (phonetic), who put this together in the last 48 hours because we realized, you know, we were familiar with this list, but maybe you guys wanted to know what is actually in the label for these products right now and whether they have any information at all.

So that is also part of the information we provided you.

Next one. Go back one, please.

I can tell you that right now we are looking at a product out of this cluster to begin development of a written request.


For neuroform, and I have clustered these because over and over again if you look at either exclusivity or the products on this list, these are two of the areas which consistently we have indication that not only is there a large amount of use in pediatrics, but also a need to have priority study.

So in here we have use that, again, this is in-patient data, varies from in the hundreds to the thousands, 16, 17,000 prescriptions for lorazepam versus our out-patient data, which again is higher, which you might expect, for the some of the treatment ADHD and lower for some of these other products. The promethazine has been on our list for a long time.

Somehow this got left off, but this is supposed to be less than two year old. The missing information is less than two year old for controlled nausea and vomiting associated with anesthesia.

And I can tell you that we have already looked at one product on this list, which it turns out for technical reasons I won't go into, but that we really can't issue a written request for it because actually part of the molecular entity may still be under patent, and we are now actively looking at a second product on this list to issue a written request for studies for this product in the neuropharm are.

Next, please.

Quickly, again, just to demonstrate the same sort of thing here in the pulmonary data and the fact that the missing information is birth to six year olds for bronchospasm has been the identified gap.

Next please.

Antimicrobials, again, we have already looked at one product on here which we will not be issuing a written request, or sometimes as you dig into these more deeply, you find that there are actually other data that you may want to develop or seek in another way.

So it doesn't mean that being on the list you will always get a written request.

And next one, please.

End up with GI, sine that's sort of where we started this morning, and as you can see, a very high use here for metoclopramide, well used for cimetidine.

Next please.

And that is a quick run-through of the 18 products that are presently on the list. It does not include the additional products that the NIH expert panel recommended because we really felt that we want to demonstrate that those were additional products that were brought up, but we wanted to at least apply the data that we could and that we had on these to our presentation today on use.

With that, having run through what our present list looks like for us to begin development of written requests and what some of the use data looks like, what the gaps are, we would ask you to answer our questions on criteria and process to help us as we move through what is really a great opportunity if we get funding, if someone would find the money for the funding of all of these studies.

But let's be optimists at this point and say that they will assume they will, and we want to move forward with trying to get these products studied.

Thank you very much.

CHAIRPERSON CHESNEY: We have an opportunity at this time to hear anybody who would like to speak in the open public hearing, and I understand we do have one speaker.

MS. HELLANDER: My name is Martha Hellander, and I'd like to -- well, you know what? I could do it from -- no, I'll come up to the podium.

Okay. Is that picking up?

Okay. I'm supposed to start with the financial disclosure statement. I never had to do this before. So it's my first time. I have no financial interest in any companies that make lithium products.

My organization, the Child and Adolescent Bipolar Foundation, has received some unrestricted educational grants from various pharmaceutical companies, including Solvay and GlaxoSmithKline in combined amounts not exceeding 11 percent last year and not to exceed five percent in our coming fiscal year.

I'm really here to represent children with bipolar disorder, and I have not even discussed this with any of our corporate donors.

I'm sure you're all aware that we've got a public health crisis in the making due to the recent enormous advances in our ability to diagnose children with bipolar disorder and, on the other hand, the lack of evidence on how to treat them.

I'm here to urge you on this committee or the subcommittee to consider placing lithium high on the priority list for testing in children, and I'd like to urge the FDA to do at least a couple of types of studies that have never been done in children and are unlikely to be done by pharmaceutical companies.

The Child and Adolescent Bipolar Foundation is a parent-led, not-for-profit organization. We have about 5,000 families now in our first three years that have joined us.

Many of us have adults with bipolar illness and several generations, and recent advances in the detection of the disorder in children offer the hope of curing and perhaps even preventing this disorder at its earliest stages.

However, the data on treatment options are sorely lacking. We urge the FDA to take a leadership role in establishing safety and efficacy information on lithium, which is off patent and has been safety and effectively used in adults for over 50 years.

A little bit about myself as Executive Director of CABF. I've consulted on the design of treatment studies for adolescents with bipolar disorder. I'm the bioethics consultant to a multi-site NIMH funded treatment study.

I've participated in strategic planning for the Mood Disorders Group at the NIMH. I've served on an NIMH review committee for studies in child psychiatry, and I'm currently a member of the Pediatric Psychopharmacology Initiative Work Group of the American Academy of Child and Adolescent Psychiatry.

My husband is an academic economist, and one more thing. The disorder has caused suicides and ruined lives in many generations in both sides of my family, both myself and my husband's family, which are also filled with accomplished and creative individuals.

One of our children was diagnosed six years ago. Her suffering, early diagnosis, and remarkable recovery well before adolescence set me down the path to help others and brought me here to speak with you today.

We've been doing some on-line surveys. We're a Web-based organization, and we've just got a new survey tool that I'm having a lot of fun with it. So we did our demographics.

So we have a rather, I think, interesting group of parents, very educated and resourceful. They have private insurance, access to great medical care. Our children are in good physical health. They're not living in poverty, and were born or adopted into loving families as far as I can tell.

Over half our members have graduated or intend to graduate from college. Twenty-six percent have graduate degrees. Most are married, and 50 percent of the spouses hold executive or professional positions.

Next slide.

I've included in the handouts an article by Dr. Barbara Geller that just came out in the American Journal of Psychiatry reporting on her two-year follow-up on a NIMH funded longitudinal study of about 90 pre-pubital kids with mania. Dr. Geller has served as a consultant or a member of this subcommittee and is also the chair of our organization's professional advisory committee.

This is the ages of the kids. They're very impaired in many crucial areas of functioning, and to learn more about the suffering of our children, I'm not going to be able to go into a lot of the details, but please visit our Web site, pbkids.org, and you can learn more there.

Okay. These hospitalization rates, by the way, about 60 percent of our kids are under age 12. I want you to keep that in mind as I speak. The hospitalization rates are incredible.

Joe Bieterman at Harvard says that 25 percent of the kids that he treats have been in the hospital, and he finds that to be just really a lot.

More than half of our kids have been hospitalized in a psychiatric in-patient unit. So, you know, this is like the end result of not having been treated and helped by medication or treatment, whatever.

Okay. Next slide.

There's three grave public health concerns that I'd like to discuss with you today that intersect with childhood bipolar disorder and which are helped with lithium.

The first one is addiction, substance use. These kids appear to be biologically vulnerable to becoming addicted, and there's a cite, and the citations are to papers that are in the packet of handouts that I passed out, and I think there's some extra ones up here for people in the back that wanted to get a copy of those.

Next slide.

As I said, there's evidence that lithium reduces adolescent substance abuse and stabilizes mood in a randomized controlled trial by Barbara Geller. It was only a short-term treatment trial, ten weeks, but she found that lithium significantly reduced substance use and stabilized mood in these kids.

The implications of this finding are quite staggering, but it has been largely ignored by the substance abuse treatment community. I have no idea why.

Next slide.

When unstable, like adults with mania, bipolar kids are impulsive and exercise poor judgment. In one study in Texas by Steven Pliszka,, he screened 50 kids, subsequently brought into a juvenile detention center. Twenty percent of them met full criteria from a manic episode. Another 20 percent met full criteria for a major depressive episode, and I think two percent had a mixed state.

If the illness is detected early enough and properly treated, this outcome could possibly or probably, in my opinion, be avoided. So here's another public health crisis for kids that involves kids with mood disorders.

Next slide.

Dr. Geller also found, and many other researchers find the same -- she studied 90 pre-pubital kids with mania. A full 25 percent of them were suicidal on arrival at her out-patient clinic. There are pre-pubital. These are kids, you know, six, seven, eight years old with serious thoughts.

Now, I need you to add if you're taking notes. Your slide may not say the serious thoughts, and when I discussed this with her, she felt that was important to put that in. I just had planner intent. So please note that.

Children often talk of wanting to make themselves dead. The don't know the word "suicide." So they say they want to make themselves dead starting as young as three or four, and they make real attempts, like trying to jump out of moving cars on the freeway.

This is the one thing that mothers compared notes, and almost all of them do that. So here's a third major public health crisis. Suicide is the third leading cause of death in the 15 to 24 year old range according to the Surgeon General that involves mood disorders.

Next slide.

Now, the 18 percent mortality rate, that's the lifetime mortality rate for this illness. That's higher than childhood leukemia. hat's higher than many cancers.

When I tell that to people, they can't believe it because most people don't think of bipolar disorder as a fatal illness, but it is. I tell you we hear every day about young people killing themselves who have been diagnosed with bipolar disorder.

The studies that resulted in the 18 percent figures, and I think actually the one in the packet says 20 percent. I was going to cite Goodwin-Jamison, but I got that mixed up. They were not in adults, but many of the adults we know to have had early onset.

Okay. Lithium is known to reduce the suicide risk sixfold to eightfold. Kay Jamison said the other day -- she's a noted person who has bipolar and is an expert on it -- she said if those numbers cam out on a treatment for cancer, it would be the front page headline in The New York Times. There is a drug out there that is off patent that reduces the suicide risk six to eight times.

We've got 25 percent of our kids that are suicidal, and it does that -- lithium appears to do that even when it's not effective in stabilizing mood, which is very interesting.

No other drugs approved for mania have been shown to have an anti-suicidal effect, to my knowledge, and I could be wrong, but I think that's still the case.

Okay. Next slide, please.

As you can see from this time line, lithium has been on the market for over 50 years, and kids with mania have been described in the medical literature for nearly that long. Yet we still have no standard treatment for pediatric mania.

In your slide, I think I have in 2000 NIMH recognizes pediatric mania, but in fact, '95 was the year that they funded Barbara Geller's phenomenology and course study. So that was they first recognized it.

And then in 2000 they held a consensus conference on pediatric mania, and they agreed that you could diagnose it in pre-pubital kids using the DSM-4. So that was a landmark date as well.

We still have no standard treatment for pediatric mania.

In your handouts is a study by Elizabeth Weller, just a sample. There have been a number of small studies, naturalistic studies, very, you know, promising and interesting, but not large.

Lithium was approved in 1970 for mania and maintenance treatment down to age 12, but at the time, no pivotal studies were ever done, and no post marketing surveillance studies or testing in juvenile animal models was ever done.

Next slide.

In a recent survey, our members reported over 40 different medications used to treat the symptoms of bipolar, none of which are indicated for children under 12, and only one, lithium, for adolescent mania.

Okay. This slide shows the number of medications our children have been prescribed during their lifetime, and these kids are mostly under the age of 18. I think there were a few 19, 20 year olds in there, but we had 854 kids of the 944 respondents to the survey. So 854 kids, and we asked each family just to respond about the oldest child if we had more than one with bipolar.

Trials of five, ten, and even 15 or more different medications are common, partly due to earlier misdiagnosis or confusion about the diagnosis.

But largely because even when they get the correct diagnosis, clinicians have no evidence based data to guide their treatment. We're getting frequent reports of kids being started on gabpentin, for example, as a first line mood stabilizer despite the fact that placebo studies in adults show it's not effective for treatment of mania and it has troubling side effects in children.

And I have a reporter calling me today who wants to talk to me about that.


This shows how many medications our children are currently talking to treat their symptoms and side effects. Let's see. How did I figure this?

Fifty-seven percent of our kids are taking three or more medications. Parents are faced with the terrible choice that they have a child with an illness that's life threatening and certainly impairing, and medications used in adults may be the only treatment available, but we don't really know what the long-term side effects might be or which treatments might have a better long-term safety profile in which children.

So we have to take the risks, but we don't know what the risks are. It's a really difficult position to be in.

But when you have a suicidal eight year old, you know, there are certain choices, tradeoffs that you will make, parents will make. That's a pretty desperate place to be.

Just of interest, the current issue of the American Journal of Psychiatry had three articles in one issue on childhood bipolar disorder, and the editorial by Fred Volkmar writes, "The lack of treatment efficacy data on these conditions is most unfortunate."

Next slide.

Of the anti-convulsants, most are still on patent, except for tegretol. The same is true of the atypical anti-psychotics and the SSRIs.

We strongly support the further testing of all these medications in children, but I'm not focusing on these other needs today since the topic of your hearing today is off-patent medications.

As you can see, lithium is being used in about 30 percent of our children, and I did hear yesterday, and I don't know if this is valid. I've been having trouble getting data on how many mentions or prescriptions are written. I heard 93,000 children in America between zero to 17 are taking lithium, but I don't know if that's mentions or, you know, currently or what.

Okay. Next slide.

In summary we believe that lithium meets all of the requirements of the Best Pharmaceuticals for Children Act, and that the urgent public health crisis of teen substance abuse, teen arrest and incarceration, and teen suicide, all of which include many kids we now know have early onset bipolar disorder, these crises call for lithium testing in children to be given the highest priority by the FDA.

In particular, we'd like to see post marketing surveillance studies and juvenile animal studies. We'd like to see requests made for these, and if proposals are not forthcoming, we think they should be appropriated if and when funds are appropriated -- I'm sorry -- they should be undertaken if and when funds are appropriated by Congress.

Next slide.

I'd like you to take one more look -- this is my last slide -- at our Web site. The little girl with the blond hair and the yellow hat was suicidal at age four, but she's been well since age ten. She's 15 now, and in high school nd wants to be a therapist when she grows up.

The little girl at the top left is now 13, plays the clarinet, and has her black belt in karate.

Both of these girls stabilized when lithium was added to their treatment, which includes other medicines currently under patent.

The boy with the turtle is Ben Harrelson of Duluth, Minnesota. He had symptoms very early in life, and like most of our kids, was misdiagnosed with ADHD and conduct disorder. He finally was diagnosed with bipolar disorder and stabilized on lithium at about age 12.

That was about 15 years ago, and he felt really well, and he asked if he could stay on the lithium indefinitely, but 15 years ago there was no maintenance data to tell the doctor how long kids should stay on lithium, and guess what. There still isn't.

So the doctor cut back on his lithium to see if he still needed it. He relapsed and killed himself before they could get his lithium back to a therapeutic level.

So in conclusion, please urge the FDA to give lithium its highest priority for testing in children, and also, I offer to be of assistance if there's any way that our organization can be of help to you or to the NIMH in this effort.

Thank you.

CHAIRPERSON CHESNEY: Thank you very much for a very compelling presentation.

Dr. Murphy, should we take a break a this point or should we proceed with some of the questions or do you have any strong feelings?

DR. MURPHY: Well, I'm a terrible task master. So --

CHAIRPERSON CHESNEY: All right. We'll move ahead.

DR. MURPHY: I would say let's move ahead and then maybe break right before we ask our European friends to speak if that's okay.

CHAIRPERSON CHESNEY: Okay. Am I reading the questions correctly, which are from your slides and the second two slides on page 2 and the first slide on page 3? Is that --

DR. MURPHY: That's correct.

CHAIRPERSON CHESNEY: Actually, Anne, could you maybe put the first question up? It has to do with criteria.

So we'll start with page 2, the middle slide. Yes, okay. Thank you.

Are volume of use and impact adequate criteria for the selection of drugs for this list? And if the answer is yes, how should impact be defined? And if not, why not? And what additional factors should be considered?

And just to reiterate, Dr. Murphy has already made the point, but we're not going to talk about individual drugs this afternoon. We're talking about the process of developing and maintaining these lists.

So would anybody like to comment on the issue of volume and impact being adequate criteria for selection of drugs? Dr. Fink.

DR. FINK: I guess I would take the negative to that and say that although they are good criteria, they were not sufficient in that -- and I think the list of drugs illustrates that -- there may be the situation which an off patent drug is replaced or is replaceable by a safer, newer drug that even carries a pediatric indication, and in that setting, even though the older drug may have volume and impact, it's not a very good one to push studying.

DR. MURPHY: So would we possibly use the criteria that there are numerous other options then?

DR. FINK: Yes.



DR. KAUFFMAN: I tend to agree with Dr. Fink in great part, but I think volume still has to be a part of the recipe that we use to select them because it is true that use doesn't necessarily mean appropriate use, and we could all pick examples off of the list we saw a moment ago to illustrate that.

But it's a beginning, and then I think we are going to have to add the other criteria that we're going to discuss subsequently to try to flesh this out and probably come up with a weighted list of criteria that will give us a scoring tool to select the highest priority drugs.

But certainly utilization or volume utilized will have to be one of them. Impact to me is going to depend on how we define that. Impact economically, impact in terms of child health in that particular disease category.

For example, there's several beta agonists on the list that are probably used much, much less commonly than albuterol. Now, should we waste resources in studying those now even though they're off patent and have some use?

Cimetidine, there are much, much better H2 blockers out there that have a lot fewer problems associated with them. Should we waste resources enrolling children in studies to study that even though it has some use?

Well, probably not, but we're going to have to have other criteria, but I think use is one of the criteria we'll have to include.


DR. GORMAN: I would like to add a suggestion of uniqueness to this list, and not to replace either volume or impact, but a drug that is uniquely indicated for disease whether it has a high therapeutic index or a low therapeutic index or is even considered to be very efficacious.

I would think of acyclovir when it first came out or perhaps one of the Alzheimer's drugs when they were the only mover in that field, that these drugs should take a place on the priority list.


DR. GLODE: I should just introduce myself to the committee because I came late. I'm Mimi Glode. I'm pediatric infectious disease from the University of Colorado.

I also agree that the starting point I think should be volume, but then I think the definition of impact should perhaps be enlarged because I would certainly agree with uniqueness, but I would also, after I looked a volume, I think I would look at the seriousness of the illness being treated, and then I would look at the therapeutic index of the drug.

So if I have a dangerous drug and a disease with low morbidity and mortality, that's a big issue to me. On the other hand, if I have a life threatening disease, you know, I again am willing to play things a little bit differently in terms of therapeutic index.

CHAIRPERSON CHESNEY: That could potentially come under impact if we define impact to include that.

DR. GLODE: Yes, yes.

CHAIRPERSON CHESNEY: Dr. Nelson and then Dr. Luban.

DR. NELSON: This reminds me of the discussions that went on in Oregon about trying to triage health care.


DR. NELSON: Pardon the analogy, but there they linked a couple of things and came up with a list, and then they used buckets. It strikes me that impact -- I might define impact a little differently and actually include volume in the definition of impact and consider impact as a combination of volume, which is both use and disease. It's not only something that is used. It's also prevalence of a particular condition.

And then severity regardless of volume, and so you end up almost with a product. Something that's severe, of low volume would be equally ranked with something with volume and low severity.

And then you end up with what I would call adjusters, which uniqueness would be an adjuster. The existence of various alternatives or options would be an adjuster. The other adjusters would be existing information that exists much on the order of the original approach to labeling.

If you've got published information and the like, I assume that that will figure into the equation, and also the consequences of misinformation in the use.

The other thing that I might add is some of the drugs on there, someone working in the ICU, it just strikes me if you're titrating the physiologic effect. Maybe I'm ignorant in my use of some of those indications, but it's not clear to me I need a lot more efficacy data for dopamine in the ICU. I just titrate it up until I get an effect. If I don't, I switch to a different drug, and there are a lo of other ones that are available to me.

So I'm not sure I would use the usage there. I wouldn't put that very high compared to other things.

And then I thought I had one final thought, but it just went somewhere else. I'll stop.

DR. MURPHY: would you repeat your adjusters.

I'm sorry.


DR. MURPHY: He had a number of adjusters, and I didn't get them all. Limited options is one and consequences of misinformation.

DR. NELSON: Options or alternatives exist. Certainly if there's -- I'm not sure I would favor newer agents. If there's better agents, sometimes actually off-patent agents are, in fact, better than the newer ones or certainly no worse.

Existing information. I mean, in ways you would make decisions about issuing either a request for labeling. Those same kinds of considerations that might exist. Consequences of misinformation.

Oh, the other thought was I just want to point out that in this arena, the Best Pharmaceuticals Act states that negative studies are in the public arena, and I want to point that out because I think that's an important component here. If we end up with a negative study, then we know pediatricians will get that data.


DR. LUBAN: I'd just like to ad another adjuster might be either adult or animal data that suggests adverse effect, and those kinds of drugs would be additional drugs to have special attention paid to them.

CHAIRPERSON CHESNEY: Dr. Spielberg and then Dr. Ebert.

DR. SPIELBERG: Following up on what Skip said, in terms of available data, I think it should be looked at both from the point of view of efficacy, you know, is there a huge literature out there demonstrating efficacy, but also on the safety side, and that comes both from published as well as AE reporting.

Is there an identified issue out there? You know, if it ain't broke, it may not need to be fixed., If it is broke, it should be fixed very quickly.

And for many of these compounds, there's already a fair amount of information out there, some of it good, some of it bad, but I think we're going to have to evaluate all of it in terms of setting priorities.

The other thing that hasn't been discussed, and this is putting on my ICH hat, there is discussion, as we'll see, in Europe now going on about similar issues with respect to off-patent medicines that are widely used in other venues than the United States.

And one of the things that I think we should be thinking about both from the practicality of doing studies internationally, sharing data around the world for all sick kids around the world, is think at least in part about the international impact of compounds.

This might be in part through the WHO essential drug list if there are drugs on that list that also appear on our list and also appear on the European list, it may provide us an opportunity for working together, getting the data more rapidly, and using it for labeling in all venues as well.

So although this is a U.S. initiative, I think since we already have participated in the ICH process, in order to make that really a live process for kids around the world, I'd really like us to consider international need as well.


DR. ST. RAYMOND: I'm Dr. St. Raymond from the European Medicine Agency.

And we had a similar discussion in our agency concerning the priorities and the needs. So it's interesting to hear you discuss because we have the same criteria at the beginning, discussing indications, severity, the use and the volume.

But for the volume, I just have a restriction that it is also related to frequency of the disease. So a drug of very little value, but very frequently prescribed, I don't want to be difficult. Auralgan, for example, may not be for me a priority because ear pain can be treated by other means, and otitis media is certainly a big problem. Ear pain is something different.

So we have this discussion. We have also discussed the needs as expressed by the pediatricians and the considered reserves from lone societies, and the first one that came up was pain and pain treatment. Therefore, we looked at whether we had a pain treatment available for all types and all severities of pain in children and for all age groups, and that's how we identify some age groups and some levels of pain treatment that were still needed, and that's where we, for example, started some studies of kinetics of codeine in less than one year olds.

And the last point that was interesting for us was considering what was said earlier that there has been a lot of published data, sparse sometimes, but sometimes available and sometimes of good quality.

It would be also a good thing to look at the fast winners, where you just need a little additional data to get a full picture of the drug rather than starting from scratch for a drug from which you know nothing.

I support also the need for new treatments rather than necessary, although we know a lot about the safety of all the drugs as compared to new drugs.

CHAIRPERSON CHESNEY: So symptoms also could come under the category of impact, where I've got pain as well.

Let's see. Dr. Ebert, you had a question?

DR. EBERT: Well, I'm not sure I have much to add to what the previous two speakers stated so eloquently, but I was going to mention that, again, I think that the volume while it is important is somewhat insensitive as a measure.

It occurs to me that medications that are used frequently may be used because they are quite efficacious, but we know little about their adverse effect profit, or they may be used frequently because they are quite efficacious, but we know a little about their adverse effect profile or they may be used very frequently because they are very safe, but we have some questions about their efficacy.

And so certainly I think the impact issue is the one of most interest to me.


DR. NELSON: A question for Steve.

Would you carry your desire for international approach to this to look at volume and severity diseases, things that aren't that prevalent within the United States? How far would you go with that assessment?

DR. SPIELBERG: In the best of all possible worlds, for sure, although there are obviously diseases that afflict the vast majority of children that outstrip anything that we have here in terms of diseases by many orders of magnitude, but some of the drugs aren't even available here, are labeled here.

So that it may make it hard from the agency's point of view in terms of those compounds. You know, I mean, when you put out numbers like two and a half million children still die of diarrhea every year around the world despite availability of oral rehydration solutions, we've got problems out there. All of the worms, all of the other infestations, all the other infectious diseases which we rare see here.

On the other hand, I would argue passionately about the smallness of the world right now. We are all very much interdependent. Toronto was interesting in that regard. I spent 11 years in Toronto with a huge immigrant population. I saw all the diseases that you see everywhere else on earth and didn't recognize them until I had seen one of them.

We all are, indeed, subject to similar kinds of things, but obviously we still have to take into account it's the U.S. congressional, as well as an FDA initiative, but I'd love to see some blend of that to be able to do some of those things.

DR. NELSON: I mean, to the extent that there may well be researchers interested in those questions that are local, but yet the population served would be international.


DR. NELSON: In many ways this list will establish RFPs and the like that perhaps having some portion of it designated so those local researchers at least have something to apply to, that would be interested in international diseases.

DR. SPIELBERG: No, I agree, Skip, and I think it's in all of our interests as human beings. It's in al of our interest health care wise. It's in all of our interest in term so world peace to decrease devastation of disease, which is going to lead to conflict.

So I think to the extent we can use such a mechanism and where it can be skillfully and cleverly applied, looking through WHO needs and looking through our needs, looking through European needs, I'd love to see it happen, indeed. I think we should try it.


DR. FINK: Yeah, the only concern I guess I have, I agree in theory with the idea of internationalizing this where possible, but I also see a major problem there that the international needs and sometimes criteria by which success is judged are so entirely different from the way they are judged in the United States.

Dr. Gorman was just advising m that rotrovirus vaccine in Third World countries will save thousands of lives, even though it's unacceptable in the United States because of a minor incidence of Ennis susception (phonetic).

So I think some of the international studies would be very difficult because we're really looking at totally different populations and a totally different background in which we are performing the studies.


DR. KAUFFMAN: I just wanted to come back to something that Skip said a moment ago because he reminded me of another adjuster maybe we could call it, and that is I agree with him that the pressers, dopamine and doputamine -- he doesn't need labeling because he's an experienced intensivist working in a premier pediatric institution, but the general surgeon in a community hospital, the general pediatrician or the adult ER doc in a community hospital who's taking care of the six, eight, ten year old doesn't have that skill, doesn't have that knowledge.

And when they go to look up information about dopamine or dobutamine today, it says, "No information available under 12 years of age." So it doesn't help them at all.

I think for some drugs, and these are probably two good examples, and we could pick a lot of others, the labeling is probably going to be much more important for certain areas of practice than it will be in the subspecialty areas of practice, and we're going to have to take that into consideration probably drug by drug.

CHAIRPERSON CHESNEY: Dr. Murphy, have we addressed the impact volume issue? I think what I hear people saying is that impact is the most important issue, and to include in that volume of use, volume of disease, disease severity, the options and alternatives.

Dr. Luban mentioned adult and animal data that indicated significant adverse effects, symptoms, including pain, as something that would have impact, and then diseases with worldwide impact.

DR. MURPHY: Of those adjusters that you just listed then, when you list a positive, then the flip side of it is a negative, if you will. So when we are looking at this, if there are no negative effects in animals, I just want to make sure. Then that would be a positive versus clearly the negative that could be then counterbalanced by one of these other adjusters, the severity of the disease, the other information that's known or not known sort of approach, but trying to think of all of those and how one could end up having a ranking with it.

They're equal is what I'm trying to say. You're considering all of those as equal phenomena.

CHAIRPERSON CHESNEY: Would we like to rank any of the adjusters under impact?

I can read them out again: volume of use, volume of disease, disease severity, availability of alternatives, adult and animal adverse event data that would indicate looking at it more carefully in children, symptoms, and worldwide disease distribution.

DR. SPIELBERG: We left off availability of data.

CHAIRPERSON CHESNEY: Availability of data. Sorry.

DR. SPIELBERG: Yeah, human data, both --


DR. SPIELBERG: -- efficacy as well as safety data.

DR. FINK: I think we left off a negative, that if there are safer, effective alternatives.

CHAIRPERSON CHESNEY: If there are safer, effective --

DR. FINK: Alternatives, that that actually would be a negative adjuster.

CHAIRPERSON CHESNEY: Okay. Anybody want to hazard a prioritization? Dr. Danford.

DR. DANFORD: I won't volunteer to put those in order, but I thought of one more that maybe we should add to the list, and that is the likelihood that an appropriate state can be designed to answer the question.

And I think back to our discussions of this morning where we had such a difficult time thinking of how we would study the proton pump inhibitors. I would suppose that pharmacologic agents that were out there for conditions in which the patients had such a degree of confounding conditions and poorly designed processes that we were treating would probably fall pretty low on our list of things we would like to investigate and those conditions that are well defined with good endpoints for treatment that could be easily studied with the idea that we would get valuable information when we were done ought to be higher priority.

CHAIRPERSON CHESNEY: So that would be a negative adjuster, the ability to design experiments to get the answer.

Let's see. Dr. Ebert, I think, was next and then Dr. Nelson.

DR. EBERT: Well, again, just potentially one other additional adjuster might be some issues of economics. I would assume that many of these agents being off label are reasonably inexpensive agents, and clearly there are some circumstances where more expensive compounds do have an advantage, but I would assume that in some cases that if one starts to look at cost effectiveness or cost benefit, that that could also weigh into the issue here.

DR. MURPHY: I'd like to say two things. I don't think the agency is going to do that. Okay? That's number one.

And, number two, I guess I have a problem with -- and I'd just like further discussion because Anne and I were getting in a sidebar conversation here about saying that because it's difficult to study or we're not quite sure, that that drug not be on the list because, number one, how do you know?

I mean, think about all of the work and the effort we've gone through with the GI drugs trying to figure out how to study them, and, yes, it's difficult, but I mean, I'm not sure whether we want to say that ought to be the criteria or two would be maybe that is an additional way to motivate because I think what somebody has already mentioned is that the products getting on this list will be -- it doesn't mean that we will ask for a written request because that's what all of these criteria are, but it does mean that there is a higher potential that they might move forward and have an RFP put out for them.

And so that approach could incorporate maybe the questions that we need answered before you actually went to the next couple of steps. So I'd just like to hear some more discussion about difficulty in designing the trial as a criteria to decide whether you would put something on a list or not.


DR. FINK: No, I --


DR. FINK: Well, my comment was actually not related to designing the trials, but I would be, I guess concerned that as we try and rank order this list we've got a lot of volume criteria there, and if we stick to that and we let volume criteria, volume of usage, volume of disease be heavily weighted, we're going to keep orphan diseases orphan diseases on our own list.

So I think uniqueness of the drug has to be weighted very heavily to compensate for the volume issues, which are obvious, but could kind of push everything else to below the threshold.

CHAIRPERSON CHESNEY: So uniqueness of the agent.

DR. FINK: Yes.

CHAIRPERSON CHESNEY: And, Dr. Nelson, I'm sorry I didn't get back to you before.

DR. NELSON: No, that actually was similar to what I was going to say. One could take this list, which you say had a list of X number of drugs, 25, 30, whatever, and then decide that there's certain subsets that fall into different categories, and it's the subsets themselves as opposed to the individual drugs that would be felt to be of higher priority.

So, for example, you could take those out that would be in situations where there are few other therapeutic alternatives available to that population of children and say that is the class which we would consider more highly than researching another class, since you don't know exactly how much money you're going to have to give.

I mean, I believe was it anywhere from two to three million to eight million that it cost to do a single study that's a PK/PD or something, Steve, something along those lines, or ten million?

DR. SPIELBERG: It's going to be very compound dependent. For drugs where we know a lot already and there is, you know, missing data and such, it could be very expensive. If the data are out there are viewed as totally inadequate and you have to start from scratch, then you're talking very large programs.

DR. NELSON: Well, basically with $200 million --

DR. SPIELBERG: But I mean, if we need some PK/PD, we can do it very inexpensively. If it's going to be, you know, a ten-year follow-up study for safety issues, you're talking enormous amounts of money. Again, you know.

DR. NELSON: Well, thinking about triaging the amount of money, you know, basically you want to have some way of differentiating on that list because there may be a need to make distinctions between competing drugs in the absence of sufficient resources to support both studies.

DR. SPIELBERG: I mean, for example, I think the issue that Ralph brought up with dopamine and, you know, folks not like you having to use dopamine, obviously, you know, I ran a quick Medline on dopamine. There are hundreds of publications on dopamine which, if, I imagine, put together with those pieces of missing data, could very readily lead to labeling under a combination of, you know, send us everything under the '94 rule because this is what's missing. Let's fill that in and get it labeled for anyone who might be faced with a child in an emergent situation.

So for relatively little investment, you might get really major return in terms of children. So I think that kind of thinking would be helpful in terms of priority because you want to think what the labeling is going to do ultimately.

You know, if it was only a drug used, say, in cancer chemotherapy by Victor, would it matter terribly much whether that information is in the label if all children are treated at, you know, COG centers, as opposed to the scenario that Ralph described of, you know, a child coming in in shock to an emergency room in a small town and there's just no pediatrician or pediatric pharmacists or reference books. All there is is the PDR, and the label may be life saving.

And those things could be done relatively inexpensively with relatively quick turnaround because there's already a lot of data out there.


DR. KAUFFMAN: I think Dr. Murphy's question a moment ago is very important, and if I understood you correctly, you were getting at the point we might have a drug that we think is pretty important and it meets all of these other criteria, but there's no way we're going to be able to study that drug for various reasons.

And one reason is an old drug that's in common use and everybody thinks they know how to use it, it's almost impossible to enroll into a study because people just don't want to do it. The physicians don't want to, the parents don't want to. It's hard to justify it.

So we will find situations, I'm sure, where all other reasons point to maybe putting that drug as a relatively high priority, but when you really think through it, it's going to be impractical to do it, and we're going to have to be sensitive and be realistic about that in some situations.

CHAIRPERSON CHESNEY: Any other -- oh, Dr. Gorman.

DR. GORMAN: Following up on that, it struck me as very prophetic that the '94 list and the 2002 list had a lot of overlap as far as agents, some of which I think the people around this table would think have very little clinical usefulness.

And I think the answer to Dr. Murphy's question is not that these agents should not be on the list, but it will determine their duration on the list in the sense that it's difficult to do studies. There may be a good reason for them to be on the list, but they'll never get off the priority list.


DR. GLODE: But, again, I think back to the issue of some of the drugs on this list are not candidates for safety and efficacy study, i.e., ampicillin from birth to one month of age. I mean, you're not going to do a placebo controlled trial of IV ampicillin for Group B strep. meningitis, I hope.

So what's missing there? Maybe just a little bit of PK/PD data is all that's missing. Ampicillin, I think its safety record in the pediatric populations, as well as adult populations, and its efficacy track record; so you could get that labeling, it seems to me, very easily. There's just a little bit of pharmacologic information missing and then that would come off that list.

So it's on the list for a volume reason, but it's not on the list for the other reasons.

CHAIRPERSON CHESNEY: Are there any other comments specifically to Dr. Murphy's question about whether the ability to design studies such as we went through this morning should automatically relegate a drug to a lower position on the list? Any other comments about that?

Anybody disagree with that statement? I think Dr. Kauffman already raised one situation.

Dr. Nelson.

DR. NELSON: There really hasn't been much conversation about process, but presumably there will be a study section of some kind that will be evaluating the proposals, and I would anticipate that it would make sense for the feasibility to be dealt with by that group rather than be dealt with on the list.

I mean, they're going to look and say this is bad science. It's not going to answer the question, and then that's not going to be funded. I mean, it's as simple as that.

DR. MURPHY: And the process could involve, you know, reporting back to that effect.

CHAIRPERSON CHESNEY: Do you want anymore input on the criteria issue or should we move on to the process issue?

DR. ROBERTS: One area that has not been addressed for developing products that go on the list and which actually Congress asked us to look at is the question of what if a reformulation is necessary to study the product in the pediatric population. Who is going to do the reformulation? And what are we going to use for the studies?


DR. SPIELBERG: That's, again, coming back to my old theme that formulation is the heart of pediatric therapeutics. It truly is.

Having struggled now on my side of the fence over making formulations, doing stability, "oops, it turned brown in four months," "oh, it crystallized out," "oh, we have an excipient that isn't acceptable in Europe and is here, and we've got to get" -- you know, clearly, the only way we're going to get standardized formulations is from a sponsor who is willing to do all of the CMC work under GMP regs., get the stuff studied for stability.

But if you think about it, that's absolutely necessary for afterwards because who is going to distribute it and who is going to be responsible for its availabilities.

You know, my 14 year old couldn't get a tetanus shot yesterday because the pediatrician didn't have it. That's pretty sobering, I must admit, very upsetting to us.

But you know, availability is entirely dependent on a supplier having that on the shelf and making it and, you know, if there's a change in GMP and having the inspectors out and doing all of the things that we normally do.

So if we do need a formulation, somehow we have to come up with sponsors, and I suppose it could be almost anyone. It doesn't have to be the originator. Sometimes it could be a small operation like Ascent Pharmaceuticals that has developed several pediatric formulations.

Sometimes it may be a larger sponsor who is looking for a compound to fit into another portfolio, but recognizing you'll only get, you know, what, three years Hatch-Waxman for the formulation. You know, I've spent sometimes as much on formulation as I've done on clinical trials. And so the incentive is low.

But it's something really that I don't think was thought through in terms of the legislation that we really do need. Otherwise we're going to fall back into the old the pharmacist makes it up extemporaneous formulation. Is it validated; isn't it validated, et cetera?

So I think it's a real quandary, and unless you can find somebody who's willing to take it on and do all of the things necessary under GMP to produce a marketable formulation and distribute that formulation and make sure it's available, we've got a problem.

DR. MURPHY: And I think what Steve is describing is you would have to write this whole process, the request and the RFP to somehow say you're going to now manufacture and continue distribution, and I think if you think about that for a little while, there would have to be a lot of money to do that.

DR. SPIELBERG: Yeah, even just to recover the cost of doing the CMC and stability and all of the other things that we normally do. Certainly NIH can't be in the business of making and marketing drugs. That's not their job.

The academic centers really can't either. It has to be some manufacturing process, and again, it doesn't necessarily have to be the sponsor. It could be a generic; it could be almost anybody, but you're going to have to find a champion who's going to be willing to do it.

And if you think about it, you know, I assume for the dopamines and dobutamines for the world, they're IV. There are formulations that are already used. We're going to be okay.

But there are certainly going to be products where that's going to be an issue, and I think it would be very unfortunate to go back to one of the old compounds and start recommending crushing and giving a tenth of a tablet. If we do that, I mean, we've just gone back 50 years. So we don't want to get into that scenario.

And if no sponsor can be found, it may end up being an exclusionary issue. It may fall off the list because something is needed and you can't find anybody to do it, but I think before giving up, I'd beat the bushes, you know, to the Ascents and everybody else, and see if it might be in their interest to pick it up if, in fact, the data are generated under quality studies done by or through an NIH mechanism.

CHAIRPERSON CHESNEY: Would a new formulation have a patent or, I mean, would they be the only people who could market it for a period of time? I mean, would that be an incentive to do it?

DR. SPIELBERG: I mean, what is it, typically three years? And with pediatric sales, you might never be able to recover the cost of R&D and manufacturing. You might be at a loss situation, in fact.

But that is a real issue, and it's one that's worried me and, I know, worried you guys, too about how to do it, and all I can think of is hopefully some of the smaller companies might find it in their interest to develop a portfolio.

You'd never do it with a single compound, but if you had a technology that might be able to do several compounds, even then, I mean, each one is looked at separately for GNP and standards and, you know.

CHAIRPERSON CHESNEY: Dr. Nelson and then Dr. O'Fallon.

DR. NELSON: Well, Steve, just to educate me, are you able to at least give a ballpark estimate if you had to develop a new formulation to what the range of cost might be to do that? I mean, are we in the two million range, the ten million range, the 500,000? I mean, where are we talking, out of curiosity?

DR. SPIELBERG: Millions, but all over the place depending on difficulty. You know, I was on one program in a previously life at a previous company that had the first protease inhibitor available. We spent three and a half years unsuccessfully trying to develop a pediatric formulation and spent a fortune bringing in every expert around the world that we could, but the stuff was a rock and couldn't be done.

DR. NELSON: Well, there's going to be outliers, but I guess the question would be could you include --

DR. SPIELBERG: It's going to be millions, and then you've got manufacturing costs, you know. Can it be unit dosed? And then you've got vial costs, and those things I don't even know what it costs to do those things.

DR. NELSON: Well, as a general impression, if you had the up front formulation cost as part of the grant, if you will, would a manufacturing sponsor be able to support the marketing and distribution costs out of the cost of the drug once it's developed and tested so that at least it will sustain itself?

DR. SPIELBERG: Right. I see what you're saying, yeah. I don't know enough on that side of the business. We'd have to get some input from the CMC folks to know if that's even feasible, and again, I guess it would vary a lot.

I mean, if you can provide 50 mL bottles of the stuff, no problem. If you have to unit dose it, very expensive. If it can't be done as a syrup, it has to be done as a chewable tab or a blister pack or whatever. Each of those things dramatically increases the cost.

So I think it will be a case by case basis, but I mean, that's something to consider, but I don't know if Congress envisaged funding formulation development because it would have to be done by a sponsor that has GMP standards and FDA, you know, qualified labs.

DR. ROBERTS: Actually, the act only talks about formulation in two places. One is that it should be considered in developing and prioritizing the list, and then once the third party does the study, when they report back, if they feel that a formulation is necessary for the product, then that should be part of their report.

And then we are supposed to send a letter to the sponsor about the product and say --

DR. SPIELBERG: But you see, that would require additional clinical studies on the formulation.

DR. ROBERTS: -- a formulation has been recommended that you did.

DR. SPIELBERG: But then you need both formulation and clinical studies on the formulation, at least bioequivalents in adults or --

DR. ROBERTS: Yeah, you'll need that.

DR. SPIELBERG: Which isn't a lot compared to the cost of the formulation development, but it is cost.

DR. O'FALLON: It seems to me we've got two different things going on here. One of them is an issue of need for treatments for certain things, and the second issue is the cost of doing business, of trying to do the studies, and they may be feasibility studies, such as issues such as we were talking about this morning. They may be financial issues, such as the formulation issues.

But it seems to me that there are a couple of things going on here. First, we should be advising the FDA on how to identify or prioritize -- what would you say? -- areas that need to have treatments for children.

And then after that, they can go about the sub-prioritization based on some of these other feasibility issues.

CHAIRPERSON CHESNEY: Any other issues like formulation, Dr. Roberts?

DR. SPIELBERG: The only other thing to mention under formulation, if, indeed, we're to keep costs down, the clinical studies should be done with the formulation that's going to be used or you're going to have to repeat it all, or at least repeat the PK and bioavailability and bioequivalent stuff, and you for sure don't want to do that.

And the other thing is if, indeed, the need is the small babes and the only thing available is a 75 milligram tablet and the estimated dose in those small babes is going to be, you know, eight, you know, a milligram per kilogram or something like that, you can't do it until you have that formulation. You're absolutely stuck. You can't go forward.

And if we did with extemporaneous formulations, I think that really would be a negative for all of us to go back to the bad old days and do that.

DR. KAUFFMAN: Question. I have a question for the FDA folks. Is there -- do you think there's the option under the act that you could separately bid the formulation apart from the study contract? In other words, so that a CRO could pick up the study part, but you would contract for the formulation with a company that had all of the infrastructure and expertise to do that rather than one entity having to pick up the whole thing?

And would the public funds pay for formulation, pay that cost?

DR. ROBERTS: Well, this is really not an area that we have discussed. It sounds like since clearly the third party who does the studies is support to report back as to whether they feel a formulation should be made, and then the agency is to issue some kind of letter to the sponsor who makes the product that it's been recommended that a formulation be made. There's no requirement.

Congress was seen -- I don't know what they thought we were going to use for the studies is my problem.


DR. KAUFFMAN: It's a big hole in the hat.

DR. ROBERTS: Yeah, it really is.

DR. MURPHY: And I think actually what we're trying to say is that certainly where we have formulations that are already available, that we could then do the studies by appropriate mechanisms because if we have to make a new one, we will.

Where we don't, I don't think we're in the situation where we have to say, well, we can't do anything. I mean, I know, Steve, none of us want to go backwards, but sometimes maybe the initial step is to develop the studies in whatever solution that you may have to develop and then study that for stability and see then the second process that Rosemary is mentioning would be the way you would go.

There would still have to be those studies that aren't that hard. I mean, you know, the stability and the bioavailability, I mean, those things we could do. So I think --

DR. SPIELBERG: Those are relatively inexpensive compared to the rest of the problems.

DR. MURPHY: This whole formulation issue, I think we clearly are not quite clear how we're going to implement it at this point. When we get to the first situation where we, you know, are going to not have a formulation, we're going to have to look at, you know, a lot of things like the possibility of doing other approaches, carving out parts of it.

And I think for right now it was important for Rosemary to put it on the table that we have to look at that, but that's been an issue, as you all know for written requests and for the rule, both, where, you know, we can ask for it, but it doesn't mean we always get it.

DR. SPIELBERG: Just one final thought on it because I am sitting next to my international colleagues. Most kids in the world don't have refrigerators, when we're thinking about international formulations, and I remind our chemists of this all the time because we have one situation where we have this great liquid, but when it's put out into a truck and transported, it degrades unless you have a refrigerated truck.

Well, that's fine here, but it really isn't fine in most of the world, and that's really a challenge that I have to keep reminding myself of and my colleagues in industry, that if we are, in fact, to treat kids around the world, we need formulations that can be used around the world.

DR. MURPHY: I think our colleagues from Europe are going to hit you on the head with a refrigerator, but --


DR. MURPHY: -- they didn't know they were lacking them.

DR. SPIELBERG: In Europe, but they're frigid. They're small. So there's no room for the medicine.

CHAIRPERSON CHESNEY: Thank you, thank you.

I think the process is much easier. Comments about -- let's see. Maybe we could have the second question.

Dr. Willoughby and Dr. Murphy and Dr. Roberts have described a process that includes use of databases, professional organizations, and an expert panel or panels. Are there other sources that the FDA and NIH should consider in the development of the list? And how should the sources be weighted?

And Section B, how can the committee make their recommendations happen in a timely fashion? And what information would be important in reporting on the progress?

So let's start with the first part, which is: are there other sources? And if I could make a comment to that, I think Dr. Kauffman mentioned the dopamine issue for the small community hospital where there was nobody available that knew anything about dopamine.

And I wondered if we couldn't also include such professional organizations as emergency room physicians, family practitioners, nurse clinicians. There are many nurse clinicians out there who are in primary care practice who don't have ready access to physicians all the time.

And then if I could also just suggest that all of the subspecialty organizations be required on some kind of annual basis to put this on their agenda and review what's happened in the previous year and be expected to get their recommendations to you in a timely fashion, but those are my comments.


DR. SPIELBERG: And not to forget AAP. I assume that was assumed, but the AAP is key in coordinating all of that.

CHAIRPERSON CHESNEY: That's sort of a given.


CHAIRPERSON CHESNEY: So lots of other suggestions here.

Dr. Luban and then Dr. Glode and then Dr. Nelson.

DR. LUBAN: Well, one group that we didn't discuss at all is fetal medicine, and I'm not sure how much applicability we have with at least what's on the priority list now, but should that list change, I think we need ACOG representation in any kind of review, particularly if we're dealing with any kind of fetal medicine.

CHAIRPERSON CHESNEY: Excellent suggestion in terms of intrapartum HIV drugs, intrapartum Group B strep drugs, among others.

Dr. Glode.

DR. GLODE: I'd just like to second your suggestion that subspecialty organizations be addressed because I think the subspecialty organizations working with just a smaller database of their own medications that they are familiar with can kind of synthesize the issues about impact from their experience would be very good.

I wondered about if there's a list of approved orphan drugs under the Orphan Drug Act or something and someone has gone down that list and looked at the relevance of those drugs to the pediatric population and, again, seen if any of those would be important to look at.


DR. NELSON: I think that what I'm going to suggest may be implicit in some of the areas, such as the FDA internal process and how individuals on the expert panels might go through their work, but I would want to make explicit sort of an evidence based evaluation of the literature and what exists and the like, you know, using sort of a formal analytical approaches, papers, that sort of thing rather than just a bunch of experts saying, "Well, I do it this way."

We assume it's literature based when an expert says that, but I would want to make that explicit instead of implicit.

CHAIRPERSON CHESNEY: Can I add one more comment to what I said? When I talked about emergency room physicians, I don't think that -- I mean, we need pediatric ER physicians, but particularly adult ER physicians who are doing a lot of the pediatric care in the community.

And in small, backward communities like Memphis, one of our major teaching hospitals uses adult ER physicians to oversee the care of children. So I'd like to be sure that we don't just include pediatric specialists, but generally ER physicians.

Dr. O'Fallon.

DR. O'FALLON: I'd just like to follow up on what Dr. Nelson said, but extend it. Remember databases are only as good as the data or the studies or whatever they came from. So if you're going to be trying to put together databases, and I do think that's a great idea, I think they also need to be evaluated, that is, the strength of the evidence, the quality of the study to produce the data needs to be evaluated, and that information needs to be involved in the database so that you're going to be able to tell whether it was anecdotal case history stuff or whether it's, you know, a highly well done clinical trial or anything in between.

CHAIRPERSON CHESNEY: Dr. Fink and Dr. Kauffman.

DR. MURPHY: Could I just say one thing?

I do want to just reinforce that within each of the divisions in these products are physicians who have tremendous technical expertise and do read all of the literature they can get their hand on before they even move forward down this list.

So I do want to reinforce that that is a process that's already occurring. So it always warrants reemphasizing, but it does occur as part of this process.

DR. O'FALLON: Is it published? Is it available to the one who reads it?

DR. MURPHY: Do our medical officers publish their reviews? Yes, we put them up on the Web.

Do they get them in the medical literature? Yes, occasionally, but again, often because their reviews are initiated because of an application, it is in response to a study that has been done by others.

And so unless there is some sort of cooperative agreement that there's an issue that would not cause a conflict of interest for FDA, they would not be publishing on that specific area.

CHAIRPERSON CHESNEY: I have Drs. Fink, Kauffman, Rodriguez and Chesney.

DR. FINK: Just to the groups that should be included, I guess, I'm not sure what the proper terminology would be, but to some degree orphan disease associations that are too small to have reached the mantra of professional organization. Because if we exclude them from this process, they're going to probably go directly to Congress, which would really bypass the process and make it worse.

CHAIRPERSON CHESNEY: Are you thinking of disease other than what Dr. Glode was -- she was talking about the list of orphan drugs.

DR. FINK: Yeah, I mean, the neurofibromatosis association. There are a lot of them out there, and they need to have some option for input or at least to state their case. They shouldn't be weighed as highly.

CHAIRPERSON CHESNEY: Oh, okay. Subspecialty groups. I'm sorry. I misunderstood the list versus the subspecialty groups, and that would include like the group that we've heard from today.

DR. FINK: Right, but obviously I think you want to let all groups that want to have a voice have a voice not just --

CHAIRPERSON CHESNEY: Yes. Thank you. I appreciate that. I misunderstood.

DR. LUBAN: Dr. Chesney, if I could just add, there is a national organization of rare diseases which exists and has broad based representation for orphan diseases, and that would be an excellent group.

CHAIRPERSON CHESNEY: Dr. Murphy, you got that? I didn't know about that.



DR. KAUFFMAN: I was just going to suggest the USP has been maintaining evidence based database on pediatric indications and dosages and so forth for years, and that database is a wealth of information. It's not the sole source of information by a long shot, but it has a lot to add to this and to borrow from.

So I would suggest we work with the USP on this also.


DR. RODRIGUEZ: It's interesting. We're thinking in the same lane. They had provided a list of drugs where there was a need for information. There was also a -- I'm talking about U.S. Pharmacopeia -- narrow spectrum, low spectrum, et cetera. I mean a wide spectrum, et cetera, et cetera, all that information.

It's interesting. Eleven of the 19 drugs that we actually flashed there were actually in their list independently developed, which in terms of going at it from a different way, we never touched bases until somebody publishes the list.

CHAIRPERSON CHESNEY: I had just two other suggestions. One is the otolaryngologists who treat probably more otitis media than the pediatricians, and the other is the child psychiatry organizations which we heard about today. I think that's a very, very important group to include, and we've already discussed issues in this committee relative to that.

Dr. Santana.

DR. SANTANA: And this may be like a restatement of a fact that's so logical it shouldn't be restated, but to pay attention to what the European colleagues are doing because if they have a similar list with similar studies, we shouldn't be expending our resources on duplicating something that's going to be so logical in terms of adapting it to the U.S. population.

CHAIRPERSON CHESNEY: Do you need more ideas?

DR. MURPHY: The process as we see it right now would be that we would look at various needs. We have a product that's on the list. We develop a written request for it. We send it to the sponsor.

The sponsor says, "I don't want to do it."

We work with our NIH colleagues to turn it into an RFP, and then there would be a section study involved with reviewing the RFP. At that point studies hopefully will be done, and then that information will come back.

Is there anyplace in that process that this committee wishes to provide further input I guess would be one of the questions we have for you.

CHAIRPERSON CHESNEY: So the decision would have already been made that this was a high priority drug in terms of being studied, to go through this whole process? That decision would have been made right up front; is that -- go ahead.

DR. NELSON: I would think that in thinking about limited resources and triage, if you're sending out written requests, say, on 15 drugs that all fall into somewhat different classes, and then let's say the sponsors all say, "No, thank you," I would think that a study section would have an easier time evaluating that if they're seeing them grouped to where if you've got limited resources you're looking at Proposal A versus Proposal B versus proposal C.

So I guess it just raises a question about the timing of the process, that if it's going out sort of one by one by one by one, you might just run out of money when you finally see something that you would have wanted to fund, whereas you had funded something earlier that you might have decided would have been a lower priority

So some thought about how you look at it all together when they come in, I think, needs to be considered, unless they give you all the money you want and it's not a scarce resource.

DR. SANTANA: Or unless all of the requests are made at the same time from the FDA perspective.

DR. NELSON: Well, if they go out at the same time and come back at the same time, they can, but I can't imagine you're going to be able to produce 15 written requests all at the same time, but maybe you can, but I doubt it.

CHAIRPERSON CHESNEY: Any responses to Dr. Murphy's question about what the role of this committee might be?

We've made lots of suggestions of other people and other organizations that could provide input, but what might our role be?

DR. LUBAN: I was actually going to reflect on what Skip mentioned. I think you can probably draw a parallel to a standard study section at the NIH, where you attempted to let them all out at once with deadlines so that they all came back and your study section group or the equivalent of counsel would assist you in prioritizing them after they've been reviewed, but before they were let.

So, you know, it's exactly a similar parallel to what happens with NIH, and then we could serve or some fraction of us or some of us with individual added expertise could serve as a counsel.

CHAIRPERSON CHESNEY: A good suggestion. Any other suggestions?

Dr. Glode.

DR. GLODE: I was just wondering whether it would be worthwhile commenting on, as we have now suggested, all of these other organizations. One of the issues that comes up, do you just ask these other organizations to develop their own list and check it against your list or do you, in fact, send out the current list and say, "Now open for comment. You know, please comment and if you see missing items that should be on here," might be an easier process since you've already gone through lots of organizations to get to this current list?

CHAIRPERSON CHESNEY: Well, we probably all have thoughts about that.

Dr. Nelson.

DR. NELSON: I think if you are going to send it out for comment you should make explicit the ways in which the list was developed, the kinds of criteria we've talked about, the various categories, and basically ask the individuals commenting to specifically address how their recommendations do or do not meet those criteria. Because otherwise you will just end up with people advocating, as they should, for their own particular interest.

CHAIRPERSON CHESNEY: My thought would be that the organizations had each year to indicate whether they had new drugs that they wanted to be considered or added and why they fulfilled the criteria.

I'm not saying when the first list came out. I happened to have been on the Committee on Infectious Disease at the time, and it was just overwhelming, and we really just couldn't even deal with it, and it's a much different list now.

But I think if you had asked us what drugs do you think need to be better studied, and so on, we would have been able to cope with it better than we were being given a list and then asked to address issues on the list, if that makes any sense.


DR. GLODE: But was that list for 500 that you were looking at? I think it's different because what's missing from these 19.

CHAIRPERSON CHESNEY: Right. No, I agree with that, but I think if you independently ask a group of emergency room physicians what are the five drugs that you find yourself most often frustrated because you don't have good pediatric data, instead of saying to them, "Here are the ten that we think you might be interested in," I think if we could make them take the initiative to tell the agency what they need help with. Just a thought.

You had asked, I think, in here about committee recommendations for facilitating timely input. Any suggestions? Timely input from all of these organizations with respect to how the list is developed. Any ideas?

DR. MURPHY: Well, I should mention to this committee, as you know, you're going to learn tomorrow you're now going to be scheduled to meet is it quarterly, Rosemary? Three times a year. So it may be a moot question, but just if we have an appeals process, that will be brought to this committee. So when you think about is there any additional input you'd like to have as far as we get input from other groups and we are producing additions to the list or taking this off of the list, we could present it to you annually or we could present it, you know, as an issue if there's an issue, or we simply -- well, I think those are sort of the two options, present it to you annually or present it because there's an issue about whether we would want to move forward with some of the criteria that you suggested and we're sort of stuck.

We don't want to add 50 more drugs, and does the committee have any other suggestions as to, you know, how they would use their criteria that they have suggested and apply to those 50 more drugs that we've gotten that people want, that we can identify had missing information, and we have the utilization data, et cetera. Is there any role that you would think you would play in that, or do you want to just wait and see how we work through the study section issues?

I mean those are all options.

CHAIRPERSON CHESNEY: I saw a couple of hands here. Dr. Fink, did you? You didn't.

Dr. Santana.

DR. SANTANA: I was just going to address the issue of clarification. I didn't understand if what you were addressing was what kind of information you would bring back to us to keep us in the loop or what kind of information you would bring back to us to make a judgment.

To me those are two different things. The latter is more the study section model and in which you have an independent body that helps you resolve the things that the study section can't resolve in terms of prioritization or allocation of cut lines or things like that.

To me that's very different than coming back to the committee and saying just like you did today, "We don't want you to look at the list and tell me whether it's appropriate or not. We want you to help us figure out whether the process is working okay or whether we need to change the criteria in terms of what's important or not important."

To me those are two separate issues, and I need to get a clear point from you whether we should be addressing both or just one or not.

DR. MURPHY: Well, we will report o you annually as to where we are because we think that's part of this committee's contribution in pediatric drug development, is understanding where we are going, what kind of information we're getting, what kind of products are getting studied. So we will report to you annually.

I think since this process now involves NIH and study sections, is there any other activity that you would think you should play? And the answer may appropriately be, no, let's see how this plays out.

But the other option would be would the committee consider if we went out, as I said, and we asked all of these people, additional groups, what are your top five drugs, and we ended up with 50 more products.

Maybe one of the things we would do is come to you with a new list, and this time we would say, "We'd like you to think about the criteria that you told us to apply and see if you can help us in resorting or ranking these 50 other products."

That may not happen, but I'm just asking if this committee thinks that is an appropriate utilization of your time and interest, and any thought, you know, about it.

Because you're right. It is a very different activity

DR. NELSON: I think you may have started to answer the question that I had, which is what the kind of nature of an appeal might be. I could imagine a group like this, if not this group, being involved in an appeal about the list partly because this is a public discussion and lists are public items and having that kind of discourse around the list may be useful.

But I can't imagine an appeal of a negative funding decision of an NIH study section. So --

DR. MURPHY: No, I didn't meant that.

DR. NELSON: So I just wanted to be clear that at that level, since the feasibility and the science and all of those things are part of that decision, then I can't imagine an appeal of a negative funding decision if someone has applied to an RFP.

It sounds like you agree.

DR. MURPHY: Yes. It really is asking your thoughts about your role really in that activity as I described where we have lots of possibilities, and clearly as you've heard we think it's inappropriate at this point to try to deal with this mechanism with 500 drugs.


DR. KAUFFMAN: I'm still a little bit, I guess, confused and uneasy because of that. We have a very daunting or you have a very daunting task in front of you with a January 4 deadline to come up with a prioritized list, the NIH and the FDA.

Working with this group on an annual basis isn't going to get that job done in the next six months. How do you see the next six months playing out? And what is the process within the agencies going to be, and how do you anticipate using whatever experts or organizational expertise that we all talked about here in this next six-month period?

And will you need to publish your draft list for comment at the end of this period and have analyzed or responded to all of the comments by January 4th for the final list?

I'm just asking. What is the process that's going to take place over the next six months between the NIH, the FDA advisors, and so forth, under the Best Pharmaceuticals Act mandate?

DR. WILLOUGHBY: I think you've outlined a problem that we're struggling with right now, and you, if you think about it, have given us a lot of good advice about how we might address that problem.

Right now there is a cadre of lawyers who are interpreting what the act may or may not be interpreted to say about that issue

DR. KAUFFMAN: Well, that should take six months at least, shouldn't it?


DR. KAUFFMAN: That's a mistake right there.

DR. WILLOUGHBY: Well, no, it can't because, you know, there isn't a choice just like there isn't a choice about the fiscal 2002 money. It's going to go forward.

But we are working within our institute on that problem right now and, in fact, have a consultation scheduled with other institutes in NIH, which of course represent different disease processes than the ones we think about in child health, also to ask their input in that process.

But my guess is that it's going to be a generation of a list and then vetting it with multiple organizations, and how we're going to deal with the issue of everybody is going to ask for the drugs of interest to them, I think, is going to be a problem.

On the other hand, I don't think we want an endless process of generating lists and then doing nothing at all.

I also can't see, although I would have to ask the lawyers, whether there's any appeal to the process at all. I mean, there's always informal appeals, you know. You write the director of the institute; you write the Director of NIH; ACOG writes the Director of NIH, those kinds of things.

But I don't envision a formal appeal process like is specified for someone whose grant is not funded or someone whose contract is not funded. I don't envision a need. Again, I'll put that to the lawyers, but I don't think that's going to be on the table.

DR. KAUFFMAN: Will there be --

DR. WILLOUGHBY: Sure, yeah, but as opposed to a binding appeal process, no.

DR. KAUFFMAN: Will written requests be issued during this six-month period while the list is being generated or are you going to hold off on written requests until a list, prioritized list, is generated, or can that go on simultaneously, in parallel?

DR. MURPHY: As I indicated, we are working off of the present list to move forward as we've been asked to do, begin to utilize this new mechanism and actually see what some of the issues are going to be, and we'll probably have a very different assessment a year from now as to what we, you know, think is working or not working.

But the answer is we are proceeding with these 19 products to, as I indicated, begin issuing written requests for some of them. Some of them we will not be issuing the requests for because, again, just because you list them doesn't mean that we're going to be able to for all sorts of reasons that have been brought up around the table today. But we are going to try.

So, yes, we are moving forward, but that's why we're calling it the preliminary priority list, because we think we need to do that while this other process will continue to move forward, collect input, and publish a list.


DR. GORMAN: Continuing on Dr. Kauffman's nuts and bolts approach and trying to echo something that Dr. Nelson said earlier, as well, there must be a limit to how many written requests you can issue. If this becomes endless, or it must have some natural limit.

Perhaps it shouldn't have any natural limit, now that I think about it, but the number of written requests will have to be limited by the resources available inside the agency, and then the number of studies that can be done will be limited by the economics of the sponsors, the sponsoring companies and the fund.

So what I'm asking is: is there some conceptualization at the two agencies as to how many of these you are hoping to do?

If we generate a list of 600 drugs or even 50 drugs, how many will be reasonably done at the end of five years, realizing that only has seven variables and three dependent questions in there?


DR. WILLOUGHBY: You've hit the nail right on the head. As was pointed out earlier, there's $200 million of authorized money which has not been appropriated. This process also is getting underway at the time of the so-called soft landing for the NIH, when the doubling of the NIH budget is stopping.

So there absolutely will be a rate limiting activity, which is pretty much going to be determined by the money available, the money available to act on the preliminary 2002 priority list is about $7 million. We don't have identified money in any budget for next year to pay for additional funding of meritorious applications that come in in response to RFPs. So that part is not mapped out yet.

DR. MURPHY: I just want to make one comment about the number of written requests. Please do not take the number of written requests that we have issued already as the rate at which we can do this in the future.


DR. MURPHY: Because, again, we started with this massive data, four to 500. We were issuing written requests en blanc. In other words, there was nothing studied in the anti-hypertensive. So we issued eight, ten written requests for anti-hypertensives.

So don't try to take those numbers like I just did and come up with we could generate 60 a year because it's not a comparable. We're not in the same place in time or a comparable process.

I think that what we are finding as we have begun to work on this 19 is that if we got one a month out, we would be doing well. And I don't think that's going to happen, and that's really driving everybody to do all of this background research, you know, getting all of their experts together and trying to work through that study design process.

So, again, I think you're right. Our limitations on how many we can generate in a year is, I think at this point -- this is just a guess. I don't want to see this that I said we can never do more than this, but right now, I would estimate one a month because we're not going to have these numerous sponsors to which we would be issuing the same written request.


DR. GLODE: I'm assuming, but I may be wrong, that your written requests differ with regard to what you're asking for, and I'm wondering with each drug if, in fact, categorizing them in terms of information needed, you know, is there or isn't there a pediatric formulation right now or is that an issue for this drug? Is a large safety study an issue? Is efficacy an issue, or is just PK/PD an issue for this drug?

And then you tailor the proposal to just what you sort of need for that drug, which, again, sort of is a priority issue, too, that the easy ones -- I think there are some you could get off this list.

DR. MURPHY: We've been looking.


CHAIRPERSON CHESNEY: You can tell who the list makers are around the table, crossing things off.

Dr. Gorman, I think you had a question.

DR. GORMAN: No, it was just I was trying to connect the dots. I understand other government agencies try to do this occasionally as well. If I use a dot that Dr. Spielberg gave us several years ago that it takes between three and $5 million to study a completely unstudied drug in pediatrics and I take the dot that you've got one program a month and $7 million, after two months we'll be done.

So I'm not sure in the sense that after that any written requests that come out have the potential to be unfunded.

DR. MURPHY: Steve, please fix that number for us because the range is quite different.

DR. SPIELBERG: Ranges vary. I will tell you without breaking confidentiality, you can add zero behind some of the programs that we're now involved in and more for a full pediatric development program.

And you know, the old saw that you saw -- bad choice of words -- the information that was being put out on the standard, you know, PK study, you know, $190,000, that was based on doing adult normal volunteers.

You take that into the pediatric population just because you have to do it in, indeed, the right kinds of pediatric centers, et cetera, and because you have to develop new analytical methods for micro volumes, et cetera, et cetera, even the cost of doing that kind of simple PK study goes up way high.

So, again, cost of studies are very, very dependent on the number of patients. I just finished a study of 150 kids at 90 centers. Okay? It was one, point, you know, three kids per center, but that means that I had to send out monitors to every one of those centers whether they were recruiting or not, and every time they recruited we obviously had to make sure of the quality.

So it required sending out QA people, as well as clinical monitors. So costs can, indeed, be extraordinary.

And, again, you know, that's why the issue with these older drugs for which we do have a lot of experience, and I agree that some of that experience may be absolutely wrong. Some of the literature may be absolutely useless, but if we're going to do this right, we really need to take maximum advantage of everything that's there and, again, fill in the gaps.

And there may be some compounds where the cost of the studies are going to be relatively modest. But, again, remember those studies are going to be done in pediatric patients at good centers, and that does add on significant to the cost and well it should because we want to get this done right. We don't want to use the standard adult PK normal volunteer model. This just doesn't apply here.

But the issue is going to be to take full advantage of everything that exists and then define the critical missing information, not what would be nice, but what really is critical, what would harm a kid coming into an emergency room with dobutamine, or is there even though -- you know, I don't know the field. I don't deal with these drugs -- but is there actually enough information out there right now to write a cookbook for a guy in an emergency room of how to use it based on everything that's now known, as long as you know how to monitor blood pressure and urine output.

So, you know, I think for each of these that's why in a sense Dianne has a daunting task ahead to get each one of these done right, to ask for the information that's needed, to not ask for too much, and also certainly not to ask for too little because at the end of the game, we want to be able to write good labels for these drugs.

DR. MURPHY: I did want to put a different boundary on it though because when I was trying to find our report to Congress, we asked a number of people besides PHARMA, CROs, you know, what the boundaries are on costs, and there are, as everyone keeps saying, there are some studies that are in the less than $1 million for children, and I think you all know there have been some states where we've been able to get good PK information.

DR. SPIELBERG: Sure, and again, if we have a lot of guidelines already, we're not starting from scratch.

DR. MURPHY: Exactly.

DR. SPIELBERG: We have a lot of previous information, and all you want to do is validate something, you can do it very inexpensively and get those bucks to spread across many, many compounds.

So doing the older compounds, particularly on the basis of good information and particularly since we have safety information accrued over time, both FDA's AE reporting, as well as what's in the literature, that will help us hone down and be much more specific than if we're working with a new chemical entity.

CHAIRPERSON CHESNEY: I think Steve makes a very good point in terms of the dopamine issue and the emergency room. So there may be a lot that we can do with what we have, even though it hasn't been technically tested.

I understand the question you're asking us, which is how do you really prioritize these with respect to importance.

Dr. O'Fallon.

DR. SPIELBERG: How badly is the data needed? And I think that's going to be the issue with each of these.

DR. O'FALLON: And I think we've lost sight of the fact, I think, that we made suggestions up front that there were certain components or criteria that would be considered important, and it seemed to me someone mentioned briefly that there be perhaps a score, some sort of a scoring system that be developed that would help to rank the need for these agents.

And then within that, then there would be this business about how much bang for the buck can we get here. With a couple of little things in here, we can fill out this one and get that one, get something in this area.

It seems to me it's the area, the disease area that needs the criteria, and then there might be two or three different agents that would be, you know -- are possible candidates for treatment in that area of disease.

It just seems to me that you've got to go back to the importance of the disease defined as not just volume and severity, but some of these other issues as well.


DR. WILLOUGHBY: I wanted to make two more comments on the fiscal issue. One is that we have a number of networks, as do other NIH institutes, that already have infrastructure support and populations recruited. So we may be able to maximize some of the dollars' usage by going to these networks and offering an opportunity for the study to be done there if the sponsor declines.

Also, if the sponsor wanted to do a study and wanted to come to one of our networks and propose it, that's something that could be considered as well.

I can also tell you that as you well know from Civics 101, the federal budget is a year-by-year item. I know what it is for this year for this activity. It's about $7 million. I don't know what it's going to be for 2003 or who's going to weigh in on that issue.

So, you know, we're proceeding because we want to be ready to seize the opportunity if it's there. Are we worried? Absolutely. But, you know, it's something we've done before with other diseases and other mandates and other concerns.

CHAIRPERSON CHESNEY: I think the comment about networks is maybe another criterion, something else we could add to criteria, because somebody mentioned this morning the neonatal network, and if it would be very easy to feed a drug in and get an answer relatively inexpensively into one of the networks as you described, that might be, again, a reason to cross it off the list. It's easier to do.

DR. WILLOUGHBY: Yet another issue is sometimes advocacy organizations can be brought in to offer co-funding if they're interested in a particular drug. It's not a huge volume; it's not a frequent occurrence. But, you know, on a single drug, it might be important.


DR. KAUFFMAN: I just can't remain silent being a member of the PPRU network and let you by with saying it would be really cheap to do this in the network.

The only way it's cheap to do it --

CHAIRPERSON CHESNEY: I didn't mean to imply that.

DR. KAUFFMAN: The only way it's cheap to do it in a network is when the individual sites in the network subsidize the study, which we can't afford to do anymore. So it still costs to do it.

Plus, if we do the whole study without a sponsor, we have to set it up, monitor it, do all of the record keeping, all of the GCP monitoring, write the report, you know, do much more than we do if we're just working with a sponsor.

So I wouldn't walk out there saying we can do it cheaply in the networks. You do have an infrastructure that gives you a place to start. You have a patient base. You have investigators and so forth, but that doesn't mitigate that much of the cost of doing the study de novo.

DR. SPIELBERG: Yes, Ralph brings up a good point. When we're quoting costs of studies, those are external costs. Those are not all of our people inside, the FTEs that do all of the stuff that Ralph's talking about, monitoring the studies, QA, statisticians who write up the statistical stuff, medical writers, all of the stuff that's necessary.

I mean, you're really starting off with no GCP infrastructure to lead to a labeling process. So these are different kinds of studies, and so those personnel are going to have to be generated somehow.

CHAIRPERSON CHESNEY: Forgive me. I misspoke.

Dr. Willoughby.

DR. WILLOUGHBY: No, you didn't. You're right about what you say about the PPRUs, of course. There are other networks that NIH supports, neonatal intensive care network, the maternal-fetal network. NIMH has some research networks. We have an adolescent trials network. We have an HIV clinical trials network. We have a global network.

I think one of the things that's going to be important to do is with each one of those networks, make sure that pediatric drugs are on the radar screen, and to see what advantage we can take of money already set aside in a network that might be interested in doing, you know, one of these studies.

So you're absolutely correct in what you say about the PPRUs, but I think there are other networks where this might work out more easily, of course, if you can interest the committed groups of investigators who are there after a competitive process to be invested in doing that study with the resources that they already have.

DR. KAUFFMAN: The difference between the PPRU network and the other networks is the other networks are fully funded through the institute for the work that they do for their protocols. The PPRU network has infrastructure support that depends on additional support for doing the individual studies.

So regardless of which network you use, there would have to be funding allocated for the cost of doing that study within that network. That was my only point.

DR. WILLOUGHBY: That's true, but what about if the interested group of investigators says that they'd like to move to the top of the list for how they're going to use their $6 million for the study of a particular drug? We can't force it, but we can ask people to consider it.


DR. LUBAN: One additional potential source might be the PCRC as well. I don't know whether you -- I mean, they're sort of an NCRR, and nobody thinks about them too much, but that's infrastructure that's already supported, as well.

Oh, Pediatric Clinical Research Centers would try the pediatric parts of the general Clinical Research Centers' GCRCs.

CHAIRPERSON CHESNEY: That's an excellent suggestion.

We have one such center in Memphis, and they're always asking us, you know, "Don't you have any studies that we can do through the center? Don't you have any studies?"

Their funding is dependent on a number of studies. That's an excellent suggestion.

Dr. Murphy?

DR. MURPHY: Thank you.


DR. MURPHY: No, really, we've gotten not only some good suggestions, but also some daunting reality testing once again, and we do appreciate all of the thoughts that the group has provided to us.

I did want to make sure we did get to hear from our colleagues from Europe though, and we are required by law to give you an update, for those of you who can hang in here. So I didn't know if you wanted to take us up on that break. I guess you need to ask the committee.

CHAIRPERSON CHESNEY: Do you want to take a break or do you want to --

DR. MURPHY: I would ask if the committee wants -- we mentioned before, Julia and Agnes. Can you stay 15 more minutes, ten?

What do we need, a five or ten-minute break?

CHAIRPERSON CHESNEY: Let's take a ten-minute break, and don't anybody leave before we meet our European colleagues.

So we'll be back at 20 after five.

(Whereupon, the foregoing matter went off the record at 5:07 p.m. and went back on the record at 5:20 p.m.)

CHAIRPERSON CHESNEY: Dr. Roberts is going to introduce our European visitors to us.

DR. ROBERTS: We're very happy today to have two people from Europe whom we have worked with, Dr. Julia Dunne, who's up at the podium.

And Julia was a member of the expert working group for ICHE-11, and that's where I first got to know her and to work with her, and currently has just recently taken a job with the European Commission.

Dr. Agnes St. Raymond, who is seated there, is with the European Medicines Evaluation Agency in London, and Agnes actually came and spent a week with the then pediatric team, which was all of five people, and we were still part of the Office of Drug Evaluation IV.

And she is working very hard over in Europe, along with Julia and several others, on the initiatives that they have ongoing, and we asked them to update us and you all as to where they are with respect to their initiatives.

Thank you very much for coming.

DR. DUNNE: Thank you, Rosemary, and thank you very much to the FDA for inviting Agnes and I to come to speak to you today.

Agnes and I are very excited, Steven, to be in a room that's lit by electricity because coming from Europe --


DR. DUNNE: -- it's quite a treat.

DR. SPIELBERG: I'll never live this down.

DR. DUNNE: It's quite a treat.

DR. SPIELBERG: Actually we had to feed the gerbils at the break though to keep them in the wheel.

Dianne asked me to give a very quick overview of the European Union and its legislation.

Next slide, please.

And you've got quite a bit of information in one of your folders of background. So I'll just highlight the points which are of relevance to our pediatric initiative.

So currently there are 15 member states, and they are listed right there. And you may not be aware, but by 2004, there will be another ten. So there will be 25 members states.

Next slide, please.

And for those of you who prefer your information in sort of pictorial form, this is a geographical map of the EU at the moment with 374 million citizens.

Next slide, please.

And after enlargement, that's what it will look like with 450 million citizens.

Next slide, please.

The European Union is built on an institutional system, and it's the only one in the world that operates like this. And the member states delegate sovereignty for certain matters to these independent institutions, which represent the interests of the union as a whole.

The basic institutional triangle is up here. So you have the European parliament, the council of the European Union, and the European Commission, and very briefly, for the purposes of our later discussion, the European parliament comprises directly elected members from the member states, and it shares legislative powers with the European Council. So it is responsible for agreeing legislation.

The council of the European Union is the main decision making body, and it embodies the member states. So member states' representatives usually at ministerial level, Secretary of State level, are on various councils which deal with different issues, such as health or industry, enterprise, economics, that sort of thing.

And then the European Commission, whom I'm representing today, is described as the driving force in the system in that it initiates the legislation.

Next slide, please.

And the European Commission comprises a college of 20 members. These members are known as the Commissioners, the European Commissioners. There's a President and Vice President. They're appointed by the member states, and approved by the European parliament, and they have a five-year term.

And then the administration is carried out by a sort of European civil service, which comprises general services, such as legal services, and the Directorates General, and we fall into the DG, Directorate General, Enterprise. That's where the Pharmaceuticals Unit is. And each Directorate General has a Director General.

Next slide, please.

In terms of the legislative process, there are three steps. The commission makes a proposal. This is adopted by the competent institutions. In our case it will be the European parliament and the European council, and then the member states implement the legislation.

Next slide, please.

And that just gives you the article of the treaty establishing the EC, which sets out the sort of legal text that we have. So we have regulations and the example there given is the regulation which establishes the European Medicines Evaluation Agency, and the centralized procedure we have for authorizing medicines.

Regulations are legally binding, word for word, in the member state. And we have directives. The directive cited there is one which embodies a lot of our -- a codified directive embodying a lot of our pharmaceutical legislation, and directives are implemented in the member states with national provisions. So there's more flexibility with a directive.

And then there are decisions which are legally binding, and the Commission will issue a decision, for example, to give a central marketing authorization for essentially authorizing medicinal product.

Next slide, please.

The stages in the legislative process are that, first, there is the Commission proposal. I won't go through this slide in detail, but it's the Commission's right of initiative, although sometimes the Commission is prompted to propose something by the European Council, for example, nd before the Commission finalizes its proposal, it will consult.

Now, there are no strict rules or formats as to how it should consult, but it will consult the stakeholders before finalizing its initial proposal.

Next slide, please.

The legislative procedures, there are four different ones, but the ones that interest us are the co-decision procedure where the European parliament and the European Council are co-legislators on an equal footing. So we have to have agreement from both the European parliament and from the European Council -- that's the member states -- in order to be able to get our legislative text adopted.

Next slide, please.

And then an implementation phase depends very much on the type of legal text, whether it's a regulation or directive. A directive, as I've said, has scope for subsidiarity (phonetic). That's where things are delegated won to the member states, a sort of more decentralized way of doing things, and there would be separate national provisions for that.

Whereas with the regulation, you have to refer directly to the provisions in the regulation, and there's no flexibility at all.

There are always time limits and obligations to notify the European Commission about complying with and adopting and implementing legislative texts, and there are infringement procedures if the Commission discovers that a member state has not implemented a regulation or a directive.

Next slide, please.

Getting onto our current initiatives in the area of pediatric medicines, you'll notice we're slightly more circumspect, and ours is called Better Medicines for Children --


DR. DUNNE: -- rather than Best Medicines for Children, but the proposal came as a result of the same recognition that is universal really, that there's a lack of suitable medicines for children, and there had already been various national initiatives in different member states, most notably in France and in the U.K.

And then initiatives at the level of EU. So there was a round table organized by the European Medicines Evaluation Agency in 1997 where a number of recommendations were made, including a need to consider having incentives and some obligations and other supporting measures in order to improve the situation regarding medicines for children.

There was also support by the EU for the development of the ICH guideline, which has already been mentioned, and in the year 2000, there was a council resolution under the French presidency. Every six months a different member state has the presidency of the council, and this resolution invited the Commission to make proposals regarding incentives and regulatory measures and other supporting measures to provide better medicines for children.

In addition, the European Medicines Evaluation Agency set up the pediatric expert group which Agnes will talk about.

Next slide, please.

The timing of the consultation, why did it happen when it did? Well, we already had some experience from the European regulation on orphan medicinal products, which was adopted in 1999, and we had seen that in the EU incentives can also work for small markets in rare diseases.

And in April 2001, the clinical trials directive, or the directive which really adopts good clinical practice in clinical trials in the EU was adopted, and that now provides an underlying harmonized framework for clinical trials in the EU, which include trials in children. And there are specific measures within that directive to insure the protection of children in clinical trials.

The Commission is also undergoing a review of its pharmaceutical legislation and the proposals for the amendments to the legislation were finalized at the end of 2001, and it was realized that it would not be possible within the scope of the review to do what was felt to be necessary to improve the situation for pediatric medicines.

And it was felt that what was needed was a separate regulation just for pediatric medicines.

Next slide, please.

So at the end of February 2002, the Commission consultation paper was released, which I think you have a copy of it in your pack. And the consultation paper itself followed a brainstorming meeting with the member states, and that meeting identified common aims and objectives, and which were put into the consultation paper, as well as possible solutions to the problems which we find ourselves in.

I might say that we had hoped that we would get some benefit from the measures which were being taken in the U.S.; that some of these studies which had been done in children and had enabled you to label products, that some of those might be submitted in the EU.

But unfortunately, that didn't seem to have been the case. So it looked very much as if you get what you pay for, and perhaps we ought to do something about it and not rely -- well, we clearly couldn't rely on benefitting from what had been done in the U.S.

Following the release of the consultation paper, the Commission encouraged input from stakeholders by having workshops and informal meetings, for example, with the pharmaceutical industry, and the consultation period closed at the end of April.

Next slide, please.

These will look familiar to you. These are the possible solutions that have been put forward in the consultation paper: incentives for industry, and this includes an extension of intellectual property provisions for medicines that are still within the patent; and a new idea, which was to help encourage adaptive medicines for children for old medicines which were off patent, which was a new marketing authorization specifically for a child orientated indication or product, and that would be a new marketing authorization. It would be entitled to a new period of exclusivity, but it would only be for that pediatric indication and not for the whole product range.

The consultation paper also raised the issue of legal requirements for companies to perform studies on new products which were in development, and it also discussed public funding possibilities to perform research on old medicines where it was thought that it was very unlikely that even the proposal of exclusivity for pediatric indication would stimulate research by a sponsor.

The next slide, please.

The consultation paper also considered having a central database for clinical trials, well, for existing and future treatments. There is already in the clinical trials directive provisions for a clinical trials database, which we are writing the guidelines for at the moment.

So all clinical trials which are conducted in the pediatric population where at least one site falls within the European Union, those trials will all be entered onto a database, the access to which is restricted to the member states, the Commission, and the European Medicines Evaluation Agency.

This other database, which is referred to in the consultation paper, would be accessible to the public and, again, has not been fully explored yet, but in principle would be a database of existing and possibly future treatments.

The other proposal is to have a new EMEA expert group, which is actually established by the regulation, and that this group would be asked, for example, to identify priorities, advise on trial performances, suitability, quality aspects and new formulations and maybe organize tenders for research contracts.

And it was also the proposal in the consultation paper that there should be a European Union pediatric network created.

Next slide, please.

Underlying all of this, it will be important for the regulation to insure compliance with the ethical principles which are already set out in our clinical trials directive. We want to insure with the regulation that we avoid as far as possible the conduct of unnecessary trials, and we are aiming for a harmonized approach across the European Union, and to use the existing EU structures, but to adapt them to the needs of this particular case.

Next slide, please.

So where we are at the moment is that we have received all of the comments. We had over 70 sets of comments. They were all constructive. Not all commentators agreed entirely with the content of the proposals, but no new suggestions were put forward. So it didn't look as if we had left out any brilliant ideas that other people had.

And the current stage is the preparation of our Commission proposal, which will be a draft regulation, which is being done at the moment, and this will be presented to the Health Council. So this is the council of European Union health ministers, which is on the 26th of June. It will be presented orally.

And it is hoped that between July and September the proposal will be adopted, and then we will enter the co-decision procedure, which is extremely complicated and long, and I think it's at that stage when we receive the amendments from the European parliament and the amendments from the European council that we will begin to get to grips with the real problems that our regulation or our proposed regulation will cause.

This for us is very useful, this meeting, because by listening very carefully to what you're saying, we can perhaps anticipate some of the pitfalls and maybe try to avoid them in the writing of our regulation.

Thank you.

Agnes will now present on the pediatric expert group.

CHAIRPERSON CHESNEY: Thank you very much.

There's a distinct burning smell over here. So plugs were being pulled out and put back in, and that's what happened to your slides momentarily.

DR. ST. RAYMOND: Thank you for inviting us today to share with you the experience we have already in our expert group.

And as I said earlier, it was very interesting to hear you discuss your needs and the priorities because we had this very similar discussion already.

And as Julia has presented, in addition to the complexity of having a consensus of experts, we had the complexity of having harmonization from 15 member states with different histories, different comparators, different level of health care, different system of health care, and different therapeutic strategies and reimbursement schemes.

Next please.

So I will try to go quite fast through the introduction, which is that we have two systems of marketing authorization in the EU. One is centralized, giving an authorization for the 15 member states in one goal, and the other is the national authorization followed by recognition by the other member states, which also allows for marketing authorization similar in the 15 member states.

So two competing systems to simplify everything, and at the end, as you can see, when we have a centralized authorization, we still have 11 official languages. So every decision is translated, what we call the SBC (speaking a foreign language), distinguishes your product information as a different package insert that is for the patients in 11 languages and the labeling on the box.

Next please.

We don't have the FDA. We have a different system. The European agency is serviced by 250 people, but we also work in the network with national agencies and there are thousands of national experts. So we have a system which at the same time lighter for some things and much heavier to manage than you have here.

Just to go through this quickly, the importance here is that the EME coordinates the scientific expertise and the resources of the member states.

Next, please.

So just a simple design of what you have. You have the expert at national levels. You have the institution that Julia has described. At the center you have the EMEA with the management board and executive director and various sectors, but we also deal with veterinary medicine, but we don't deal with food, nor medical devices.

And we have three scientific committees for the time being, one in charge of the human medicine, the CPMP; one in charge of the veterinary medicines, CVMP; and one more recently created in charge of the orphan drugs.

Next, please.

The CPMP is a scientific committee for human medicines, is comprised of two members per member states. So that's 30 members, plus a chairman, plus three or for observers from Norway and Iceland who are not part of the European Union, but are still willing to enter one day, so are observers in our system.


The CPMP is meeting every month, and for four days, and of course, this committee cannot see -- it is dealing with all marketing authorization, preauthorization, authorization, and post authorization, including pharmacovigilance. The committee has a lot of work to do, and works with working groups that meet on a regular basis with a different frequency depend on the group.

And you have the group for biotech products, a group for pre-clinical safety, a group for pharmaceutical quality, what you call CMC, a group for blood and plasma work, blood products, and a group for efficacy, which is dealing with most of the guidelines that we show on therapeutic indication, such as hypertension, for example.

And in addition, you have some expert groups that are adult expert groups that meet depending on the need, and the pediatric expert group is part of this working groups that work on an ad hoc basis.

But you have also I mentioned two or three of them on the HIV products, for example, and a recently created of bioterrorism.

Next please.

So we said we were 375 or four million inhabitants in Europe in the 15 member states, which mean that we have about 75 million children. The situation is exactly the same as it was in the U.S. some years ago. The drugs used in children are not studied nor assessed.

And I've quoted one or two references. The most ancient one dates back to '87, and more recently, the issue of the 1st of June of 2002 in the BMJ you find also some results for the Netherlands and from Germany on the use of medicines in general practice.

And all of them describe the same situation: use off label or unlicensed, in particular, for products that are used as extemporaneous preparations in hospital pharmacies.

Next please.

So I will go through this one, please.

So this expert group has been created last year. It was decided to create it in May. We received proposals from the various member states, too, for the experts, and the first meeting was in September 2001. It was two other meetings, December and February this year, and the next meeting is at the end of this month.

The objectives of this group are waiting for the regulation to come to start working on the pediatric development of drug, and this includes coordinating at a centralized level, the European level, the national actions and trying to get information from the national actions that have been taken in order to harmonize this action and try to I would say seed, have a sort of seeding system for the other member states.

And we want also to improve what is given as advice in the guidelines, the existing guidelines, because most of the guidelines that are actually available are aimed at adult diseases and don't include any mention of whether or not there is a pediatric indication and whether or not you can extrapolate data from the adult indication or whether or not you need to perform separate studies and in which age groups.

The second aim is more ambitious. It's to define the need and the priorities for the studies of products, which is exactly what you've done this morning.

The third aim is to obtain some information and to make this information available, in particular, by using your Web site, a common Web site to all member states, and this is just starting with the aim of having this information available to everybody, including the public.

And we have started also to develop a network of relationship with the patient organization with industry. We're meeting with industry next month -- I mean this month -- in two weeks' time to see with them what is available currently, what practical solution they can offer us and how we can -- for example, we know that some of these companies in Europe have product that they have never brought to marketing authorization authorities, and they have this dossier in their fields, and we would very much like to see them.

We also would like very much to see the U.S. studies that have been performed and never submitted to the European authorities.

And we also when we mean learn societies, we're developing a network with the European Confederation of Pediatric Specialists to be sure that we have the proper expertise all the time in various domains because our group is a very small group.

Next please.

It's actually comprised of 14 experts, which is not much, and we have one representative from various committees or working parties because we want to make sure that what is done in one group is consistent with what is done in our group.

So we systematically invite people from quality, to be sure that what we will do with them on pediatric formulation will be translated into the proper guideline, including medicines in general for adult or elderly or children.

As I said, the experts were proposed by the member states, and the decision was made for the groups not to have what is the normal way we constitute a group in the EMEA. We take one representative per member state, which means obviously if one member state doesn't offer an expert, we are not obliged to have one per member state, but they have the opportunity to have one per member state.

And this time we create a sort of revolution because we decided that we want some expertise, and we define a priori the need that we wanted.

Next please.

So we decided we need someone that would be able to talk about pediatric formulation, but also have the proper link with the outside world, and actually we have one pharmacist with part of the European Society of Clinical Pharmacy and with the hospital pharmacy they can relate with this network.

We have one pre-clinical expert plus someone from the safety working party, and you will see in the next slide what we asked them.

We have taken one expert. This is an arbitrary choice of taking Bayesian methodologies, but the idea was to have someone interested in the methodology for small sample size because this is a very important topic. Within that we should go on with new methodologies or methodologies that are not so new, but are not so much used, in particular, with respect to market authorization applications.

And we can go away from the parallel group design.

We have some PK and pharmacology specialists. One is even a professor in Columbus University, John Von Danker (phonetic), and he's also Dutch. That's why he is a European expert.


DR. ST. RAYMOND: We have several members of various specialty neonatology because we felt it was important. Immunology; we wanted to have an oncologist, but we never found one which was available for us. They all have too much work to be there, but we know that we have the proper contact if needed.

We have also two people representing pharmacovigilance, and this is particularly important because we feel that there are a lot of issues that need to be developed in respect of the follow-up of drugs post marketing, especially for children where growth and maturation have their interaction with the long-term effect of the drugs.

And one of these experts is also an expert in vaccines. So it's particularly relevant for pediatrics, and as I said, we have also the links with the existing working parties, and we have decided at the difference of other groups to have an open group because in general we like secrecy. In the EMEA, we don't have the public. We don't have a representative of industry, and our debates are secret. And most documents are classified confidential.

So we've decided that this time the information was very important, and we have always accepted people, experts, I mean, who were interested in participating in that group and provided that they fill in the proper confidentiality agreement or declaration of interest, we open the group to people who can come and participate.

Next, please.

So for the expert in formulation, we have started working on sort of guideline. It's not much, I know, because guidelines are always guidelines. They are not binding and, therefore, nobody feels obliged to comply with them.

But at the same time, we don't have a regulation yet. So we're more preparing the work and harmonizing our views on what is needed, and we are working on the documents on the pediatric formulation of choice, in particular, with respect to excipients that can be used in neonates, infants and children.

We have used what has been published by the hospital pharmacies in Europe or a network of hospital pharmacies. They have looked at the 20 most requested extemporaneous preparations for children to see where the needs are in the hospital.

This is not representative of the public label practice prescription, but it's already a need from adult medicine that are every day transformed into some sort of mixed, crushed tablets, and IV formulation and so on.

And we feel that there is a need to work that could be also a starting point for us in the needs for children.

Although this is not the aim of this group obviously to work with extemporaneous preparations, we feel that there is a situation where sometimes it would be impossible to get to a pediatric formulation, and we have to be realistic and give some advice on how to prepare extemporaneous preparations in the best way possible for children.

But this is, as we would say in French (speaking French), by default, I would say.

Next please. I'm nearly finished.

On pre-clinical issues we have worked on the toxicity in juvenile animals. When you put together regulators, they're always happy to add requirements to industry and say do more studies. That's what we want. We feel more comfortable if we get more information.

But we have also asked the people to review the existing data of studies in juvenile animals to be sure that what we are request has an value, and I think the example of the quinolone should make us very cautious about relying too much on juveniles anymore because the data were in a way informative, but also in a way not informative.

Next, please.

A methodology. This small sample I just alluded to is a common problem also with orphan drugs. As I am already in charge of orphan drugs, we have decided to have a meeting, an inventory of the existing method of what would be applicable to a medicinal product. The meeting will take place in October of this year in the EMEA.

Next, please.

For the needs, I mentioned it earlier in my intervention, and I think we are currently trying to harmonize what has already been done by the U.K., France, Sweden for information on extemporaneous preparations, the existing compendiums that are for pediatric drugs and some of the U.S. studies, provided they are submitted, and we are trying to define the best way to find needs at the European level, knowing that there might be differences between the U.S. and Europe as regards comparators, the way that people are treated on each side of the Atlantic.

We know it's difficult. Some people have failed to do so, and we are perfectly aware of that and trying to make it simple and to make it arbitrary because we can't be fair. We can't include everybody. We know that will be too much.

And so we've tried to look at the main area. I mentioned pain, for example, to be sure that we have treatment of painful children for all age groups, and that would be the first way into the needs.

This is also in preparation of the public funds that are planned into the regulation, the new regulations, and where the fund will be available, we want to be ready to do the studies by having already defined the needs.

Next, please.

But yet as I said, we have tried to develop and set some guidelines how to follow and where to follow, what should be the endpoints to follow drugs in children.

next, please.

We plan to have that basis also in the regulation, and we want to, as soon as we get the information on pediatric drugs, to put it on the Web as much as possible, and we are very keenly asking the European Commission to have the right to put every information obtained through the incentives and including negative information.

I mentioned the pediatric EPARS. That would be a way out, not including the information in the product information, but to have a sort of scientific summary similar to what we have already for all products that are approved centrally, where you have a scientific summary, scientific basis for the positive -- the granting of authorization.

And we feel that there might be the possibility of having such a resume, such a scientific summary on the Web that would explain what was a study, what was its result, whether there were negative or positive, and without necessarily introducing that into the product information.

Next please.

So I'm finished. So we've started to work in a practical way in a small group with limited means, but people are very enthusiastic, and I think we can at least prepare for the regulation because, as you know, our legislative process takes several years before it comes to force.

Thank you.

CHAIRPERSON CHESNEY: Those two presentations were superb, and it seems miraculous to me how much you've accomplished given 15 member states and having to get all of those people together, to agree, and the superstructure you've developed is incredible.

DR. MURPHY: Agnes, I learned something. I always learn something from you, but I was particularly taken with I guess Julia made the comment or you that the products that we have had labeled are not getting labeled in Europe. Is that -- I mean that is something maybe we should pursue as a joint thinking process because I think clearly the ethical issues involved in not conducting additional studies is important.

DR. ST. RAYMOND: I mean, it's quite a problem. We don't always know, and if there's any way we can check on your Web site to find out what's been authorized, and then we ask to find out whether anybody has submitted in the EU because it wouldn't necessarily have to be a centralized authorization.

But we have found out that these studies just aren't being submitted, and I did once -- I didn't do it personally, but I asked a pediatric pharmacist to contact the company because I knew that they had recently got an authorization for pediatric formulation of a particular product which would be very useful, and he contacted the company and they said they have no intention of submitting an application anywhere in the EU. They just got their authorization in the U.S., but they have no intention of submitting it in the EU. And they didn't give them a reason. They didn't have to.

But it's very, very disappointing.

DR. MURPHY: It's quite disheartening.

DR. NELSON: but it's entirely rational. I mean if I was advising a sponsor, I would say wait until the legislation would give you exclusivity in Europe so that you get additional cash. So I'd wait a few years for the process to take place and then submit it.

DR. ST. RAYMOND: Yes, but we're not going to give it retrospectively.

DR. NELSON: So you're going to repeat the same studies that have been done?

DR. ST. RAYMOND: No, no, but it's unlikely that they would get exclusivity retrospectively. These provisions will come into place once it's been adopted, and it may well be that it's off patent. So they won't be able to get a retrospective --

DR. NELSON: Right. I mean, it would still be on patent at that time.

DR. ST. RAYMOND: Well, I don't think it will in this particular case because this is already a couple of years ago. It will be another couple of years before our regulation comes in.

CHAIRPERSON CHESNEY: Dr. Murphy is going to give us a five-second update.

DR. MURPHY: I will try to go as quickly as possible.

The Best Pharmaceutical Children Act we will not talk about anymore. As I said, tomorrow we will receive training, and Dr. Roberts is going to say something at the very end of the session about what you guys can expect tomorrow.

The next slide, please, Anne.

We also wanted to make clear to everybody that the pediatric rule remains in effect. If you live outside the Beltway, this probably wasn't a big to-do, but inside the Beltway, it was quite a raucous for a number of weeks because FDA has been challenged by the Association of American Physicians and Surgeons in the Competitive Enterprise Institute and Consumer Alert that we lack the authority to enforce the pediatric rule.

I will not go into any further statements on this, except just to say that at the end the Secretary of Health has announced that FDA will continue to defend the pediatric rule in court and will not pursue a stay of litigation. So the rule does remain in effect.

Next slide, please.

Speaking of the rule, why do we think it's important? We think that it has contributed to the entire effect, as we have often said, of having this incentive and regulatory approach that the sum is greater than its parts or the carrot and the stick or whatever you want to call it. We think it also plays an important role, and we're finally beginning to be able to collect some numbers to look at that.

We looked at, between April 1st, 1999 and March 31st of '02, the number of applications that were submitted and whether they had waivers or deferrals or had completed studies in them for pediatrics.

I do want to digress just a minute and say that the person who ought to be up here presenting this is Terry Crazenzi (phonetic), who is our ADRA within the office and has done a wonderful job. If you have a question, I'll just pretend like I know the answer, and I'm going to turn around and ask her in the meantime.

But basically we feel that the 94 studies complete is important because what we try to look at is can we dissect out what role exclusivity in the rule might play in this, and the cut to the chase is we can ascribe or make attribution to exclusivity, but we cannot make attribution to the rule as a matter of exclusion. So that's the best we can do for right now.

Next, please.

The reason for the deferrals that were listed is that they don't want to hold up, as you know, and by law we're not allowed to hold up the adult approval, and that we will have future studies in children, and our desire for additional data before proceeding.

Now, it may be that you want more additional post marketing data before you proceed. The reasons for the waivers were safety issues, small number of patients, concerns about this product was an OTC product. It was not self-diagnosable in children, adult indication that wasn't applicable to pediatrics. Clearly, we've gone over those in the past. That's a large number of the waivers. Certainly the complete waivers is because the disease doesn't occur in children.

The fixed combinations which we have problems with, since we don't know how to use any one individual drug properly, we certainly don't think studying the fixed combinations until we understand the individual products is always a good idea.

And then as has been mentioned, literature information, and one of the things that occurs still in this country is that studies will get done, and they will not be submitted. That still occurs.

Next, please.

Examples of indications or disease is waived. We've, again, provided this for you before but wanted to just reiterate types of disease that you would not expect to get to study.

Next, please.

This is in your handout. I'm not going to go over every one of them, but basically these were the applications that were subject to the rule, and exclusivity was granted.

And if you add these up in your handout -- if you'll keep going; the next one. There are two or three of these. Okay -- that it's about a third. So of those 90-some, because these numbers are changing all the time and everybody wants a precise one, but basically about a third of the completed studies were involved in exclusivity.

Now, Dr. Roberts has sat down and mainly gone through all of the indications and tried to say, "Well, what are the other possible reasons that, you know, might be able to exclude?" Like as a pediatric indication, or they submitted it under the old '94 rule and are just getting around to doing it or whatever.

And I can tell you, unless Rosemary corrects me publicly, that it's a very small number that you can actually eliminate. So that at the most, or I should say at last half of these products were studied because of the rule, that we couldn't make attribution because there were pediatric indications or there was some other cause or because they were involved in exclusivity.

So that's our broad, ballpark estimate at this time, is about half of these products got studied because of the rule.

Well, can we defend every single one of those? No. Again, that's a diagnosis of exclusion, if you will, for the physicians in the group.

Next, please.

I'm going to now go to the exclusivity contributions to pediatric drug development and the development of additional data.

This slide is a summary since we began of all of the proposals that we have received from industry to study products and of the number of written requests which have been issued, and of the number of exclusivity determinations that have been made that we have granted, 58 of these products exclusivity. We have denied eight of them, though we have actually gotten labels from two of these, which had useful information in them.

And we have now 36 labels that have been the result, direct result of pediatric exclusivity.

Next, please.

This is supposed to have little parens around it and say percentages. Got left off. The types of studies that we've been asking for, again, this number has really pretty much stayed consistent over the last couple of years. About a third of the studies are efficacy studies, a third are PK and safety, and the rest of them, the breakdown between the PK/PD and safety only studies.

Next, please.

We could spend a whole afternoon or more talking about the benefits that we think we have been able to define as far as labeling with the new studies, but I have provided the summaries in your handout. More correctly, Terry has provided the summaries in your handout of what the new labeling changes are that we think are particularly important because they either indicate an increase in mortality, and we did discuss this previously with this group. With propofol, they indicate that we had the wrong doses that we were using. They indicate that we had new safety issues that hadn't been described before.

So out of those 36 labels, about a third of them, and that's a fairly remarkable number, have important new dosing or safety information, and one of them we have thus far did not improve efficacy.

So the issue there, again, in response to some earlier discussion was it doesn't mean that the product actually does not work. It just didn't work at the dosage that they were studying it at, which happened to be at the drug levels that worked in adults, and that's in the label now.

But if you kept doing what you were doing, it wouldn't work. So that was what was important about it.

So the summary of all of that is a third of the products that we've managed to get studied thus far have important dosing or safety information or, in one case, efficacy information now included in them.

Next slide, please.

I am not going to go through all of these. It's ten after six, and I think that my threat that you will have to be here until eight would not be appreciated, but you all can read this. It is in your handouts.

Go quickly through the rest of them. Keep going. I think we're missing one from here.

Very final comment before I ask CBER to give an update on where they are with their therapeutics development program, is the reorganization that has occurred. We mentioned this to you last time, that we were forming a new office, and in that office would be pediatrics, counterterrorism, and pregnancy.

That did occur, and we are now placed as the office ped. with development and program initiatives under the Office of New Drugs.

We're going to reorg. again. As a matter of fact, we're supposed to have finished that reorganization this month, and we now will be reporting out of the Center for Drugs, and it will be the Office of Counterterrorism and Pediatric Drug Development.

I will come back and make a comment about why that makes a lot of sense. You've just got to expand your horizon.

And we now have a new -- because of the expansion of the program, we will have a Division of Pediatric Drug Development, which we did not have before, and we're very excited about that. And we have been given a number of FTEs to be able to grow our program within the office. So that is the big, exciting, new development, that we'll have a Division of Pediatric Drug Development and a Division of Counterterrorism.

And the link here is if you all will look at what was up on our Web page under our bioterrorism Web page, you'll see that some of the more important information that the FDA had to provide during the anthrax event was information on pediatrics. How to use amoxicillin, because people suggested using it twice a day when we knew that to mimic the animal models that were used for the adult dosing, that would not be appropriate. So we were able to provide information on amoxicillin dosing up on our Web site, and also for the preparations.

We are now developing preparations, again, a little bit to what Agnes addresses, the fact you have to be pragmatic, and when you're talking about shipping air loads of product, they aren't going to ship as much suspension as they are solid dosage form.

And so our pharmacokinetics people and our rapid response group have conducted palatability and stability and in some cases bioavailability testing of various home preparations which we will be posting up on our Web for potassium iodide and the doxycyclines.

So we think that this whole area was one which was of great concern during the anthrax terrorist events. So it does make a little bit more sense than one would anticipate in emergencies.

And I think that's al that we have, isn't it at this point? Yes.

Our Web site has not changed. Our new phone number is 301 -- we also moved just because there wasn't enough going on. We also moved and our new phone number because we don't have cards yet is (301) 827-7777.


DR. MURPHY: (301) 827-7777.

DR. SPIELBERG: That's easy.

DR. MURPHY: And if you're calling Counterterrorism, it's 7711. So --

DR. SPIELBERG: Does that mean CDER doesn't exist anymore? It's not a Center for Drugs?

DR. MURPHY: Pardon? No, no, no, no, no. We're just abbreviating to get things in the boxes, you know.

DR. SPIELBERG: Okay. It still is CDER.

DR. MURPHY: Oh, yes, yes, yes. You know, trying to create the org. charts and little boxes.

CBER, yes. We're through.

Yes, please.

DR. EASTEP: Hi. My name is Roger Eastep, and I am the Director of our regulatory information management staff.

Dr. Karen Weiss, who is our center lead and expert on the pediatric rule and almost everything having to do with pediatric issues, is somewhere in Erie, Pennsylvania with a broken down van. She was on her way back from a conference in Toronto.

Because of that I'm here and also Helen Wurst, who is the Special Assistant to our Associate Director for Policy, Diane Maloney, is here, and we're going to present the numbers and probably give you some broad statements on what the numbers might mean, but how well we might be able to answer questions that might come up remain to be seen.

Hopefully the numbers will pretty much speak for themselves. As you can see, the total numbers that we have are significantly less than what you saw for CDER, and that's not unexpected since the total number of applications we receive under the Public Health Service Act to license biologicals is significantly less than the number of new drug applications that the Center for Drugs receives.

First I should mention, and I'm sure you're all aware that the pediatric exclusivity relates only to drugs approved under 505(b) of the Food, Drug, and Cosmetic Act.

We do have some new drug applications in the Center for Biologics, but virtually all of those relate to blood banking and blood products. They're anticoagulants in blood banks; they're rejuvenations, blood additives, and so most of those are really not going to have issues as far as pediatric exclusivity.

We have not sent any written requests out, and we don't see any going out on the horizon. So primarily what we have to deal with is the pediatric rule.

And this chart has three sections in it. The first under received, I just wanted to give people an idea of how many of these things have come into us since the first of April in 1999 that we feel the rule may be applicable to based on the definition in the regs.

And as you can see, we have a total of about 50 applications and supplements, and I've indicated for each of those kinds of applications what sort of decision or determination we've made either finally or initially with regard to whether the data that's been submitted with the application is complete, incomplete, and if it's incomplete or if no data were submitted, what we decided to do with it with regard to deferring the studies or waiving them.

The bottom line is really what we have to work with. Generally what we do for the applications that come in is we code them in our system as far as whether the information is complete, whether we're going to defer, to waive it. Because we pretty much know from much earlier in the drug development process, even Phase 2 or earlier, what we're going to end up with. So most of these are no surprise.

There are a few though, and as you can see, the numbers aren't totaling up in the pending list or at the total list either at the top. There are a few that we have yet to make a decision on, and that decision, of course, needs to be made at the time that the application and the supplement is approved.

So the ones on the bottom do total up. You can see one situation under supplements there where the total is actually one more than what we indicated it was applicable for, but that's simply because the submitted and complete we had to make determinations on as to whether we were going to defer or waive it.

So we have a total so far of applications and supplements that have been approved of 23, and of those, we've deferred 13, and we've waived seven.

And we don't have any real big surprises as far as what kind of waivers we've granted or the reasons for the waivers. It's primarily based on the limited or not expected usefulness in pediatric, breast cancer, for instance. Our most recent one is botox for wrinkles. We don't expect that's going to be used in kids too much, and so that was waived.

One thing that you might note there is that we have a pretty small number in the approved column or the approved rows for submitted and complete. There's only a total of three, but the pending, and the total obviously, the proportion is higher, which suggests to us that the companies are more on board with the need to submit these up front.

So the most recent ones that are pending tend to be more likely to have completed studies.

I think the only other issue I would mention is, of course, we have vaccines in our center, and as you would expect, a lot of these vaccines are for pediatric use, and most of those we don't have these sort of issues with. If they submit an application for a vaccine, it's pretty much going to cover the appropriate pediatric population.

That's our numbers with regard to the rule in a nutshell. If there are any questions, we'll try to field them. If we can't answer them, we're going to pass them on to Karen so that she can get back to the subcommittee.

CHAIRPERSON CHESNEY: What are the two agents -- the one agent that was submitted and complete? The second column from the bottom, second one from the left.

MR. EASTEP: Submitted and complete, of the nine BLAs that were --

CHAIRPERSON CHESNEY: That were approved.

MR. EASTEP: I have a list here. I might be able to tell you.

Well, I just have our waived and our deferred list here. I don't have the list as submitted. So that's one we can get back to you on.

CHAIRPERSON CHESNEY: Not a big problem. Any other questions, comments?

Dr. Murphy, Dr. Roberts?

DR. ROBERTS: With respect to tomorrow, it is a training session for all of you. It will start at nine o'clock in the Advisors and Consultants Building. As Joan announced, you'll be taking taxicabs over there with your luggage, please.

And you will get trained on the Best Pharmaceuticals for Children Act with emphasis on those areas of the act that will directly involve you in your new charges.

And the big part of that session, since the act so nicely lays out a separate dispute resolution process for labeling, if there's a problem with labeling the information and getting agreement of what the FDA feels is necessary to go in the label as a result of those studies, getting agreement with the sponsor.

And so the bulk of the training tomorrow will be really about labeling, and it's going to be presented to you by a group of people within the Center for Drugs who actually does the new reviewer's course and teaches them about labeling.

And then we will have a representative from a Division of Marketing and Advertising to talk to you about how the language in the label can be very difficult to agree on because that's what actually can be advertised.

You will get lunch, and we will be done by two o'clock.

CHAIRPERSON CHESNEY: Thank you very much.

And I have to just say how very impressive it is, what you all have accomplished in a relatively short period of time. To have 94 drugs approved and with new labeling for pediatric use is just most impressive.

So thank you on behalf of all of us and children.

DR. MURPHY: Thank you all very much for staying with us.

Rosemary says my math is bad, that we're going into our fifth year. It just feels like I've been with you guys for the last five years.


(Whereupon, at 6:28 p.m., the Subcommittee meeting was adjourned.)