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DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PEDIATRIC ADVISORY COMMITTEE MEETING

Wednesday, September 15, 2004

8:10 a.m.

ACS Conference Room

Room 1066

5630 Fishers Lane

Rockville, Maryland

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P A R T I C I P A N T S

P. Joan Chesney, M.D. C.M., Chair

Jan N. Johannessen, Ph.D., Executive Secretary

Deborah L. Dokken, M.P.A.

Steve Ebert, Pharm.D.

Michael E. Fant, M.D., Ph.D.

Samuel Maldonado, M.D.

Robert M. Nelson, M.D., Ph.D.

Thomas B. Newman, M.D., M.P.H.

Judith R. O\'Fallon, Ph.D.

FDA Participants

Solomon Iyasu, M.D.

Dianne Murphy, M.D.

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C O N T E N T S

AGENDA ITEM PAGE

Call to Order and Introductions - P. Joan Chesney,

M.D., Chair, Pediatric Advisory Committee 5

Meeting Statement - Jan N. Johannessen, Ph.D.,

Executive Secretary 5

Statement of Dianne Murphy, M.D. 8

Subpart D Referral Process - Sara F. Goldkind,

M.D., M.A., Bioethicist, Office of Pediatric

Therapeutics 17

Summary of Deliberations of Pediatric Ethics

Subcommittee held on 9/10/04 - Robert M. Nelson,

M.D., Ph.D., Chair of the Subcommittee 26

Overview of Adverse Event Reporting as Mandated by

BPCA

\- Solomon Iyasu, M.D., Medical Epidemiologist

Office of Pediatric Therapeutics 70

Adverse Event Reporting

\- Ocuflox (ofloxacin) 105

Fosamax (alendronate) 110

Hari Sachs, M.D., Medical Officer, Division of

Pediatric Drug Development

\- Fludara (fludarabine)

Susan McCune, M.D., Medical officer, Division of

Pediatric Drug Development 125

\- Clarinex (desloratadine)

Jane Filie, M.D., Medical officer, Division of

Pediatric Drug Development 149

Adverse Event Reporting for Drug Products

Containing Budesonide or Fluticasone: Pulmicort,

Rhinocort, Flonase, Flovent, Advair, and Cutivate

\- Peter Starke, M.D., Medical Team Leader,

Division of Pulmonary Drug Products 172

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C O N T E N T S (Continued)

AGENDA ITEM PAGE

\- ShaAvhree Buckman, M.D., Ph.D., FAAP, Medical

Officer, Division of Pediatric Drug Development 190

\- Joyce Weaver, Pharm.D., Safety Evaluator,

Division of Drug Risk Evaluation 199

\- Badrul A. Chowdhury, M.D., Ph.D., Director,

Division of Pulmonary and Allergy Drug Products,

CDER, FDA 211

Open Public Hearing \--

Final Comments and Adjourn - P. Joan Chesney, M.D.,

Chair, Pediatric Advisory Committee 239

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P R O C E E D I N G S

DR. CHESNEY: Good morning. I think we\'re

ready to begin today\'s deliberations, and I\'d like

to say that we\'re not going to introduce the

committee members until Dr. Murphy has given us an

overview of the previous and current committees.

And so we really just, I think, need to start off

the meeting by having Dr. Johannessen read the

meeting statement.

DR. JOHANNESSEN: Thank you, and good

morning. The following announcement addresses the

issue of conflict of interest with regard to the

study drug, dextroamphetamine, and competing

products used for the treatment of ADHD and to the

adverse event reporting session and is made part of

the record to preclude even the appearance of such

at this meeting.

Based on the submitted agenda for the

meeting and all financial interests reported by the

committee participants, it has been determined that

all interests in firms regulated by the Food and

Drug Administration present no potential for an

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appearance of a conflict of interest at this

meeting, with the following exceptions:

In accordance with 18 U.S.C. 208(b)(3),

full waivers have been granted to the following

participants:

Dr. Patricia Joan Chesney for ownership of

stock in a company with a product at issue valued

at between \$25,001 and \$50,000, and for her

spouse\'s honoraria for speaking on unrelated topics

at a firm with a product at issue valued at less

than \$5,000;

And Dr. Robert Nelson for an honorarium

for speaking on an unrelated topic at a firm with a

product at issue valued at less than \$5,000.

A copy of the waiver statements may be

obtained by submitting a written request to the

agency\'s Freedom of Information Office, Room 12A-30

of the Parklawn Building. In the event that the

discussions involve any other firms or products not

already on the agenda for which an FDA participant

has a financial interest, the participants are

aware of the need to exclude themselves from such

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involvement, and their exclusion will be noted for

the record.

We would also like to note that Dr. Samuel

Maldonado has been invited to participate as an

industry representative acting on behalf of

regulated industry. Dr. Maldonado is employed by

Johnson & Johnson.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement in

any firm whose product they may wish to comment

upon.

Thank you, and we\'ll now turn it over to

Dr. Dianne Murphy.

DR. MURPHY: I wanted to just take a

moment to welcome everybody and to also tell the

committee that you may not have realized\--or a

number of people on this committee, that you have

just made a transition. That transition has been

from a subcommittee, which was providing very

important advice to us, but to now a full

committee, which advises the Commissioner directly.

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And you have certain responsibilities that are

slightly different, and I\'m going to go over those

in a second. And also to the fact that you are not

only just a full committee advising the Commissioner, but

that, as I said, you have certain

responsibilities that you\'re going to hear some of

them today that are clearly defined.

You have moved from the Center for Drugs

to the Office of the Commissioner, and the office

has been\--and this committee is now administered

there the Office of Science. And our new Exec.

SEC. is Jan Johannessen, who has done an

extraordinary making sure that everybody has been

recruited and met all the criteria that we need to

meet and getting you here and assembled and in

helping us charter this new committee.

It is really just a monumental feat

because the agency basically was not allowed to

have any new committees. It actually took Congress

to create you. So I\'m spending a little time on

this so you\'ll understand how important your

deliberations are to the agency.

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One of the other activities that has

occurred, as you know, is that there has been the

creation of the Office of Pediatric Therapeutics,

and that office is now responsible for all

pediatric activities across the agency. And,

therefore, this committee may be hearing more\--having been

in the Center for Drugs previously, you

may be hearing more about other products such as

devices or formula. So I wanted to make sure that

you are also aware of that.

And I know sometimes that\'s a bit

overwhelming if you\'re a cardiologist or an ID doc

or whatever your training. The breadth of what

we\'re asking you to deliberate upon is quite large.

However, as those of you who have been on the

previous subcommittee are aware, we always bring in

additional experts, that you\'re here to bring

particularly to those deliberations the pediatric

perspective, because we have lots of technical

committees that have lots of expertise, and we will

always bring that additional expertise as needed to

the deliberations. But it\'s your particular

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pediatric perspective and expertise that we depend

upon at these meetings.

I did want to spend a moment introducing,

so that you can put some faces with names, the

people who are now in the Office of Pediatric

Therapeutics, which is Sara Goldkind, who will be

speaking; Solomon Iyasu, whom you know, who has

been on detail with us for a while; Ann Myers, if

you\'d put your hand up, Ann, who is our policy

analyst, so you\'ll have a face there; and Jean

Harkins, who is not here, but she is the person who

actually runs the Office of Pediatric Therapeutics.

I mention that because it is that office

that is mandated to particularly focus on the

ethical issues and the safety issues, and that this

committee within the Office of the Commissioner has

now also been identified to deal with those issues.

I also wanted to comment on some other

transitions for those of you who have been on the

subcommittee. I\'m no longer with the Office of

Counterterrorism, Pediatric Drug Development.

Rosemary Roberts is the new office director, and so

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she\'s still going to be very active in the

pediatric issues, and the Division Director for

Pediatrics, Shirley Murphy, is now the Deputy

within that office. And we have a new Division

Director, just so you\'ll know these names. Lisa

Mathis I do not believe is here. She\'s dealing

with other issues this morning.

For the new members\--and I apologize to

the old members because I know you\'ve heard this.

I actually took it out of the slide on Monday

because I didn\'t think that everybody really wanted

to hear about all the accomplishments of the

previous committee. But I wanted the new members

to hear a little bit about what the previous

committee has actually\--some of the issues they

have dealt with. And they have dealt with not only

the ethical issues that have to do with normal

volunteers, placebo-controlled trials, the

vulnerable population within pediatrics. They have

dealt with an enormous array of scientific issues,

from sleep disorders, hepatitis C, HIV, antiviral

drug development in neonates, the current

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epidemiology and therapeutics and development of

therapies for hyperbilirubinemia, clinical risk

management for HPA axis suppression in children

with atopic dermatitis, tracking cancer risks among

children with atopic dermatitis, and as you all are

aware, last February a discussion of the FDA

process and review of therapies for major

depressive disorder.

In addition, this committee has now

reviewed\--before today\'s additional eight products

that you\'re going to be hearing about, has reviewed

over 22 products that were granted exclusivity, and

you have looked at the one-year post-adverse event

reporting that has occurred for those products. I

can tell you that this is an important process that

we are looking to evolve constantly. It came up

recently at a congressional hearing as to how were

we doing this and what were we doing with it. And

I think it\'s important that this committee realize

that it is important what you have to say to us

about whether we should do anything else in trying

to follow\--gain a better understanding of what

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happens to children after these products have been

either approved\--or approved and particularly after

they have been studied, because as you heard

yesterday, they don\'t always get an approval or a

label change, but certainly they have been studied

and they may be granted exclusivity. And that in

itself often results in additional information.

As you go around this morning, it would be

helpful if you would identify if you were on the

previous subcommittee. I\'d appreciate that just so

the new members will know. And also, I wanted to

particularly thank Sam\--and is Steve here? I don\'t

see him. Oh, there you are. As Jan said, for

doing double duty. We are still in the process of

identifying the industry and consumer

representatives, a total different process, and

they very kindly agreed to continue to assist us in

these last rigorous days, the last few days.

And, again, thank you for being here, for

your participation, because I know it requires

quite a commitment, and for your thoughtfulness as

we move forward with this new committee.

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DR. CHESNEY: Thank you very much, Dianne.

So I think we would like next to go around

the room and have the new Pediatric Advisory

Committee members introduce themselves, and I\'d

like to start with the members who are no longer on

the committee, if they could\--that was a joke. So

let\'s start with Dr. Maldonado.

DR. MALDONADO: Sam Maldonado. I work in

pediatric drug development at Johnson & Johnson,

and as Dr. Murphy said, this is my last session

with the committee. There will be a new member

from industry.

DR. NEWMAN: I\'m Tom Newman. I\'m a

professor of epidemiology and biostatistics in

pediatrics at the University of California, San

Francisco, and a general pediatrician, and I\'m new

to the committee.

MS. DOKKEN: I\'m Deborah Dokken, and I am

also new to the committee, and I am a patient-family

representative and I really appreciate

having that voice on the committee.

DR. O\'FALLON: Judith O\'Fallon. I\'m a

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professor emeritus of statistics at Mayo Clinic. I

got called back half-time to cover a maternity

leave, by the way, going back. But I\'ve been on

the committee since its beginning.

DR. FANT: My name is Michael Fant. I\'m

an associate professor of pediatrics at the

University of Texas in Houston. My expertise is in

neonatology and in biochemistry. And I\'m new to

the committee.

DR. NELSON: I\'m Robert Nelson. I\'m

associate professor of anesthesia and pediatrics at

Children\'s Hospital of Philadelphia and University

of Pennsylvania. My clinical area is pediatric

critical care, and I also work in the area of

ethics, and I was on the previous subcommittee.

DR. EBERT: Hi, I\'m Steve Ebert. I\'m an

infectious diseases pharmacist at Meriter Hospital

and professor of pharmacy at the University of

Wisconsin, Madison. I\'m an outgoing member of the

committee.

DR. CHESNEY: And my name is Joan Chesney.

I\'m a professor of pediatrics at the University of

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Tennessee in Memphis, and my interest is infectious

diseases, and I\'m a former subcommittee member.

DR. JOHANNESSEN: My name is Jan

Johannessen, and I\'m the Executive Secretary to the

Pediatric Advisory Committee.

DR. MURPHY: Dianne Murphy, Office

Director, Office of Pediatric Therapeutics, FDA.

DR. IYASU: I\'m Solomon Iyasu. I\'m

medical team leader with the Division of Pediatric

Drug Development and an epidemiologist with the

Office of Pediatric Therapeutics.

DR. CHESNEY: Thank you and welcome to all

the new committee members. You\'re in for quite a

ride, believe me.

Our first speaker this morning\--and,

again, for the new committee members, what you\'re

going to hear about next was really a historic

process and a historic meeting on Friday. And Dr.

Sara Goldkind is going to introduce the topic for

us. She\'s a board-certified internist who did a

clinical fellowship in medical ethics at the

University of South Florida. She also has a

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master\'s degree in religious studies with a focus

on comprehensive religious ethics\--comparative

religious ethics, excuse me, and she\'s been with

the agency for almost a year, which she tells me

seems like longer than that.

Dr. Goldkind?

DR. GOLDKIND: It\'s my pleasure to be here

today at the inaugural meeting of the Pediatric

Advisory Committee and to tell you about the work

of the Pediatric Ethics Subcommittee.

As Dianne mentioned, this is really a

landmark time in pediatric research. That\'s the

way we see it because we feel that this committee

as well as the Pediatric Ethics Subcommittee can

really make incredibly important decisions and

consensus statements regarding pediatric research.

So what I\'d like to do now is talk a

little bit about the role of the Pediatric Ethics

Subcommittee. It is going to be a subcommittee

that addresses Subpart D referrals and also ethical

issues that impact on research affecting the

pediatric population.

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Going back to the part on Subpart D,

there\'s a mistake in the slide, and where it says

\"Joint 21 CFR 50.54 and 45 CFR 46.407 referrals,\"

those are referrals that will come to both OHRP and

the FDA, and we actually had one of those to review

on September 10th, which involved the effects of a

single dose of dextroamphetamine in attention

deficit hyperactivity disorder, a functional

magnetic resonance study. And Dr. Nelson, who is

the Chair of the Pediatric Ethics Subcommittee, is

going to give you a summary of the deliberations of

the Pediatric Ethics Subcommittee in that regard.

The subcommittee can also address

referrals that come only to the FDA under 21 CFR

50.54, and I\'m going to talk about these

regulations in a little bit more detail. But if

there are no referrals and there are burning

ethical issues that we would like to address, we

can also take those to the Pediatric Ethics

Subcommittee for deliberation.

So now to go into a little bit more detail

about the regulations under which we can have these

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referrals, Subpart D is entitled \"Additional

Safeguards for Children in Clinical Investigations

and Research,\" and they are essentially identical

for DHHS and FDA. DHHS regs are Title 45, CFR 46,

also known as \"the common rule\" because 17 federal

agencies operate under those regulations. And the

FDA regulations are 21 CFR 50.

There is a notable distinction between the

two sets of regulations, and that is the issue of

waiving parental permission can be done under Title

45, CFR 46, but not under the FDA regulations. But

in terms of the Subpart D referral process and the

general categories of pediatric research, those are

identical between the two regulations. And what

I\'ve done in these slides is include the citations

for both regulations.

So Subpart D has four different categories

under which pediatric research can be conducted.

The first category is 50.51/46.404, and that is a

category which states that the research involves no

more than minimal risk. And it essentially does

not discuss who benefits from the research, but

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basically describes that there\'s a ceiling of

minimal risk for exposure for the children.

50.52/46.405 is research that involves

greater than minimal risk but presents the prospect

of direct benefit.

And then 50.53/46.406 involves greater

than minimal risk but presents a prospect of

generalizable knowledge about the disorder or

condition, but there\'s no prospect of direct

benefit to the participants.

So those are three categories under which

an IRB can classify pediatric research. If the IRB

determines that it cannot classify the research

under those first three categories, however, the

IRB finds that the research presents a reasonable

opportunity to further the understanding,

prevention, or alleviation of a serious problem

affecting the health or welfare of children, and

the FDA Commissioner or Secretary, after

consultation with a panel of experts in pertinent

disciplines, and following an opportunity for

public review and comment determines the

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following\...

So, in other words, if the IRB feels that

the research has merit for the general pediatric

population but cannot be classified under one of

the first three categories, it can make a referral

to one of the federal agencies\--and I\'ll discuss

those details in a minute\--to have the protocol

reviewed by an expert panel.

And so what must the research then

satisfy, according to the expert panel? The

research, in fact, satisfies one of the first three

categories, so the expert panel can make a

determination that after it reviews the research,

actually one of the first three categories does

apply, or the following three conditions are met:

the research presents a reasonable opportunity to

further the understanding, prevention, or

alleviation of a serious problem affecting the

health or welfare of children; the research will be

conducted in accordance with sound ethical

principles; and adequate provisions are made for

soliciting assent and parental permission.

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The composition of the Pediatric Ethics

Subcommittee is the following: Dr. Nelson is the

Chair. According to FACA, we also need to have two

members of the Pediatric Advisory Committee

represented on the Pediatric Ethics Subcommittee.

And in addition to Dr. Nelson, we included Dr.

Chesney and Dr. Gorman. And we supplemented the

Pediatric Ethics Subcommittee with an additional

group of core ethicists: Drs. Fost, Kodish and

Marshall.

The composition of the Pediatric Ethics

Subcommittee under both DHHS regulations and FDA

regulations states that the panel of experts in

pertinent disciplines, for example, science,

medicine, education, ethics, and law, and we

selected from among those groups according to the

protocol. But most of those groups were

represented on the Pediatric Ethics Subcommittee

that took place on September 10th. In addition, we

also had two patient advocates represent on that

subcommittee.

So once the IRB makes the determination

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that it wants to refer to a federal agency, it

refers to the FDA for regulated\--if the products in

the protocol are FDA-regulated, and it refers to

OHRP if the research is federally funded or

conducted. And we have a very close working

relationship with OHRP, and when a protocol comes

to us, we also refer it to them for review, and

they refer a protocol that comes to them to us.

And in this case, the protocol was actually

submitted to OHRP, but upon our review it was noted

that two of the products in the protocol, both the

MRI machine and the dextroamphetamine, were FDA-regulated

and so we also had jurisdiction over that

protocol.

The review would then be conducted by the

Pediatric Ethics Subcommittee expert panel, and as

I said, each protocol\--we will have a core group of

ethicists, and it will be supplemented by

appropriate expert panel members and patient

representatives and/or community representatives.

The Pediatric Ethics Subcommittee will

bring its recommendations to the Pediatric Advisory

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Committee for endorsement, as Dr. Nelson will do

today, and then those recommendations will be

submitted to the Commissioner of the FDA for final

determination. Once that determination is

rendered, it will be forwarded to OHRP, and OHRP

will send the Commissioner\'s memorandum on the

Pediatric Ethics Subcommittee/Pediatric Advisory

Committee\'s recommendations on to the Secretary,

and the Secretary will have his final

determination, particularly in regards to funding

of the research.

So our goals in this process, clearly the

overarching goal is to advance an understanding of

pediatric research, and we\'d like to do that

involving additional expert input and public input.

We also want to have transparency in the process,

and in that regard we had an open public comment

period before the Pediatric Ethics Subcommittee.

We also had an open hearing available at the

Pediatric Ethics Subcommittee. We also want to try

and respond to these protocol referrals in a timely

manner so that they will be helpful to the IRBs

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involved. And we want to be able to handle these

referrals in a consistent and clear manner so that

they can advance the general understanding of

pediatric research. And we would like to do this

and are doing this in harmony with OHRP so that we

have a united federal agency response to pediatric

research.

Thank you.

DR. CHESNEY: Thank you very much.

Maybe what we could do is introduce and

hear our next speaker and then ask for questions

from the panel. Dr. Skip Nelson is the Chair of

the Pediatric Ethics Subcommittee, and he will

discuss with us the deliberations of the Pediatric

Ethics Subcommittee with the invited folk that Dr.

Goldkind just mentioned on last Friday. And the

issue here is that Dr. Nelson has prepared a

summary of the committee\'s deliberations, which you

have in front of you, and I\'ll let him highlight

issues that he wants to bring to your attention.

And what we\'re looking for here is an endorsement

by the committee. As we\'ve mentioned, this took a

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whole day of fairly intense deliberations last

Friday, and we don\'t anticipate that we will have

to repeat that process here. So we\'re just looking

for the committee\'s endorsement and any questions

that you may have, either for the process as Dr.

Goldkind just outlined it or for the specific

events of Friday as Dr. Nelson will present them.

DR. NELSON: Thanks. You have the

document before you. Let me just note, as someone

pointed out, I\'ve got the wrong date in the

heading. That will be corrected before the final

version goes up. If you see any other typos, feel

free to write them down and share them with us

after our discussion.

I\'d like to walk you through the document.

My intent here is not to read the document but to

highlight what is in it, since you can probably

read faster than I can talk. The introduction

simply restates the purpose of the meeting and then

gives a brief summary of what\'s in the summary.

But let me first start with what is the

primary issue that would be raised by this

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protocol, which is the particular risk of the

procedures that are contained within the protocol.

Now, as a preface to this, one of the

first things that an IRB must determine\--and for

this exercise, the Pediatric Ethics Subcommittee is

effectively functioning like an IRB\--that the

research design is sound. So after I talk about

risk, I\'ll then run through a number of recommendations and

stipulations that the committee made

to assure itself that, in fact, the research was

sound. But assuming those are made, the

subcommittee felt that the following risks would be

appropriate:

The first is the single dose of dextroamphetamine.

Is that minimal risk? The feeling

was no. We can a little bit later, if you\'d like,

about the definition of minimal risk, but, in fact,

that was not minimal risk. But the subcommittee

felt that it was no more than what\'s called a minor

increase over minimal risk, and it lists the

reasons there, which I think I\'ll state in more

detail for highlight.

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First of all, it has been used since 1937

with a good safety record. It is one of the only

two stimulants that are approved down to age 3, and

the children in this protocol are between 9 and 18.

The greatest side effects are irritability,

restlessness, agitation, and temper outbursts which

generally last only 4 to 5 hours, are infrequent,

and as you\'ll see later, one of our risk

minimization strategies was to say they should do

this in the morning so you don\'t have the kid up

all night after you do this. It\'s used universally

in pediatric practice, and the more common risks

are restlessness, anxiety, loss of appetite,

insomnia\--again, why we made that recommendation.

There were two procedures we felt ought

to\--well, a second procedure that we felt ought to

be drawn out and highlighted, and that\'s the

withholding of medication for 36 hours from the

kids with ADHD. The feeling was that also could be

characterized as a minor increase over minimal

risk. The reasoning here is that kids with ADHD

often are not medicated over the weekend, often are

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not medicated when they\'re not going to school, and

are often given holidays from the drug. So it

didn\'t feel that a 36-hour period of time was of

any significant risk to those children.

And then the remainder of the procedures,

which are outlined further along, we all felt were

appropriately considered minimal risk and,

therefore, were appropriate for either group within

the protocol.

Now, the one design recommendation that we

made was to consider narrowing the subject

population that\'s part of this protocol. There was

some discussion about the variability in both

neurodevelopmental stages and then response to this

dose of the stimulant between the ages of 9 and 18

years of age, with different points being raised as

to the scientific advantages and disadvantages of

either the younger age group or the older age

group. We didn\'t feel that we could make this a

stipulation, but felt that the investigators should

strongly consider narrowing that range within 9 to

18 to get a more focused population.

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The other confounder that came up\--and

this is also in response to some points made in the

public discussion\--is that trying to tease apart

the changes that might occur in response to the

drug over time versus basic underlying differences

in terms of, if you will, the neurological

networks, that you need ideally to have treatment-naive

subjects with ADHD, or at least less ideally,

if that is a practical difficulty in doing in this

particular age group, try and get a more uniform

cohort of drug exposure, which is why we had the

discussion of picking the lower-dose range.

One reason for that was that the expert

scientists felt that often the dose over time that

you may need goes up, and if they unified the dose,

then probably you would end up with a more uniform

distribution of the length of exposure to

treatment. But we didn\'t feel that that reached

the level of a stipulation, but certainly felt that

that was a strong recommendation to consider

improving the scientific value of the study.

Now, there are a number of required

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modifications to the protocol. Point A, which I\'m

not going to read, is basically my summary of all

of the procedures in the protocol. And one of the

recommendations is\--it was very hard to find all of

these things, and it would be nice if they just put

them in one place so no one had to go reading

through it in all detail. One, for example, that

came up\--and I\'ll just highlight this\--is that

every child will receive a diagnostic MRI scan,

which is, in fact, part of NIH policy. You could

find that nowhere in any of the documentation, and

that came out during discussion. Things like that

need to be in the protocol.

I might add, what we will be doing is

depending upon both the Office of Pediatric

Therapeutics and the OHRP to make sure this

happens, so it\'s not something that we need to then

worry about.

The second point, sequence of subject

testing. They\'re not planning to do the kids that

are twins. There are discordant twins, either both

homozygous and dizygotic. They\'re not going to do

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those twins unless they see differences between the

kids with ADHD and the kids without ADHD. That

sequence of testing, which came out in testimony,

was very hard to find anywhere in the protocol, and

that needs to be included. They won\'t do the twins

if, in fact, they don\'t find a difference in the

non-twins.

It was very hard to find the right dose

since there were these dosing discrepancies, and so

that needs to be clarified. But I\'ve stated what

the committee\'s understanding is, and, of course,

if this is different\--and this is based on the

investigators\' testimony\--that will have to be

dealt with. And, again, I mentioned the morning.

A functional MRI. The protocol lacks a

discussion of what came out in the testimony of the

training that goes on to make sure these kids are

comfortable inside the machine, make sure they can

actually do the tasks that they\'re being requested

to do, et cetera, exclude kids from claustrophobia.

Not much in the protocol about that. I already

mentioned the diagnostic MRI scan, which needs to

33

be in there.

Pregnancy exclusion. You only found that

in the parent permission form. The feeling was

that that needs to be discussed in the protocol and

the child assent documents, and in particular,

mechanisms for protecting the confidentiality of

the adolescent that she may or may not want to go

into the protocol knowing that there\'s a pregnancy

test depending upon activities. That needs to be

spelled out. We weren\'t making a judgment about

how that should be handled other than the

importance of the confidentiality in soliciting

that information.

There was a significance discussion of

neuropsychological\--I would like to have questions

at the end, because what will happen is I bet you

some will be answered, but write them down.

Neuropsychological testing. There was a lot of

discussion about this testing. It\'s not being

performed for diagnostic or treatment purposes, and

we felt it would be a cleaner study if, in fact,

this information was not provided back to the

34

parents. Part of that discussion was based on it

not being done in that kind of a therapeutic

context.

And then genetic testing. There is

testing being done only for zygosity, and we felt

since there was a whole slew of markers being done

and no discussion about the risk of those markers

relative to, say, late onset adult diseases, that

the cleanest way to do that would be to destroy the

data and the samples after you\'ve determined the

zygosity of the twins, maintaining only that piece

of information.

Modifications to the parent permission and

child assent process in documents follow, of

course, those that need to be included from the

discussion of the procedures. There were a couple

of specific issues. One is payment. They were

proposing a lot of money\--I didn\'t put it in here,

but a lot of money. We felt it was too much and

that basically the parents should get reimbursed

for expenses, and that for young children, a token\--although

we didn\'t have a discussion of what that

35

is, but allowing the IRB to have some discretion,

and for older children who would be potentially

capable of working at a wage position such as

minimum wage, the wage model would be appropriate.

And, of course, consistent with FDA policy, this

would be, in fact, divided evenly over the protocol

procedures so that a child who withdraws in the

middle still gets part of the money.

They needed to pay attention to the

opportunity for dissent, particularly in the twin

pairs. We thought that the twin without ADHD could

be under some pressure to be in the study, and they

needed to provide that opportunity. And then some

clarification about the risks of the drug in the

actual consent document, and in many ways we

actually said you should overstate the risks in the

consent document. Although we do not feel that

this drug presents any risk of addiction, the

parents should know that, in fact, it\'s classified

as a drug of abuse, with an important distinction

being made by our experts between substance abuse

and addiction. It\'s one thing to say take

36

dextroamphetamine to be able to stay up for your

exams in college, but that doesn\'t lead to

addiction because generally you don\'t then want to

take it when you plan to fall asleep during

vacation. And, of course, both permissions.

Now, there were some specific questions

that we were asked to respond to, and I think for

these questions, perhaps I\'ll just read our answers

so that you get it clear.

What are the benefits, if any, to the

subjects and to children in general? There is no

direct health benefit to the children included in

the research. The protocol addresses the question

of a unique central response to stimulants in ADHD,

utilizing a better research design than previously

published studies and controlling for performance

differences. As such, the protocol may be able to

untangle clinical state and trait\--meaning genetic

relatedness\--differences through the use of

monozygotic and dizygotic twins who are discordant

for ADHD. Now, more speculatively\--and this was

part of the discussion\--the results may improve our

37

understanding of ADHD in order to enhance

diagnostic precision and avoid misclassification

and overtreatment.

Now, the types and degrees of risk that

this presents to subject, I\'ve discussed a fair

amount of that above, and, again, we thought that

all of the procedures other than withholding of the

medications and the blind administration of study

drugs were minimal risk, and those two were a minor

increase over minimal risk.

In terms of whether the risks are

reasonable in relation to anticipated benefits,

this is a key point. For all subjects enrolled in

the research, the risks to subjects are reasonable

in relationship to the importance of the knowledge\--i.e.,

the benefit to children in general\--that may

reasonably be expected to result. However, it is

only for the children with ADHD that the research

is likely to yield generalizable knowledge which is

of vital importance for the understanding of the

subjects\' disorder.

For you regulatory junkies, you\'ll know

38

that I\'m reading language that is contained within

the regulations as well, but the important thing is

then that children without ADHD do not have a

disorder or condition, which is why this then could

not be approved by the local IRB, although the

brain response of children without ADHD to a single

dose of dextroamphetamine is an important part of

the generalizable knowledge to be gained in this

research based on the first step of the comparison.

So we thought it did present a reasonable

opportunity to further the understanding,

prevention, or alleviation of a serious problem

affecting the health or welfare of children.

So, with that said, the determination of

approval categories that the subcommittee felt was

appropriate was that the interventions and

procedures included in the research can be approved

for the children with ADHD under 45 CFR 46.406 and

21 CFR 50.53. That\'s the category that says no

more than a minor increase over minimal risk; that

basically the experiences are reasonably

commensurate with those inherent in their

39

condition; the intervention is likely to yield

generalizable knowledge about the subjects\'

disorder or condition, which is true for the ADHD;

and then that there are adequate provisions for

assent.

Now, because of the lack of a condition in

the kids without ADHD, we felt that it could not be

approved under those three categories consistent

with what the IRB found. But we did feel that it

presented a reasonable opportunity to further the

understanding of a serious problem; that it would

be conducted in accord with sound ethical

principles; and that there are adequate provisions

for soliciting assent and permission. And as such,

we recommend that the involvement in the research

of children without ADHD is approvable, assuming

all of the required modifications are made, under

46.407 or 50.54.

Then one final point. It had been brought

up in some of the public testimony, the applicability of a

particular case known as Grimes v.

Kennedy Krieger Institute. Whereas, normally or

40

often we might anticipate that the kinds of studies

that come before us are going to be multi-institutional,

multi-site, and multi-state and

we\'re not going to want to get into the business of

commenting on the legal interpretations of all of

those different environments, we have the unique

situation here where this is a single site located

within Maryland, and this is a fairly high profile

court decision. So prior to the meeting, I had

asked for clarification by both FDA and OHRP

attorneys about the applicability, and the feeling,

which I agree with and I think some other

knowledgeable members of the subcommittee that I\'ve

talked with also agree with, is that the holding is

not applicable for two reason: One is NIH is a

federal enclave and not subject to state law; and

second is when this case was considered,

reconsidered, the Maryland Court of Appeals stated

that \"the only conclusion that we reached as a

matter of law was that, on the record currently

before us, summary judgment was improperly

granted.\" So attorneys have a term called \"dicta,\"

41

which means basically the judge expressed opinion

on other matters, but, in fact, those other matters

are not binding as law. So for those two reasons,

it was felt that we did not need to get into the

issue of the applicability of this particular case

as a subcommittee.

So, with that summary, I guess how about

questions about the document, the protocol and the

like, and then after that, I certainly would be

interested in any more general questions about the

process, if that\'s a reasonable approach.

T1B DR. CHESNEY: We actually have a visitor

this morning. Dr. Bern Schwetz is the Director of

the Office of Human Research Protections, and I

wondered if we could call on him to come and make a

few statements before we invite questions.

DR. NELSON: Sure.

DR. SCHWETZ: Thank you very much, Dr.

Chesney. I just wanted to express my thanks for

FDA and this Advisory Committee creating the

opportunity to do this joint review in one process

rather than have the FDA and OHRP going in separate

42

ways to review a protocol of this kind where

there\'s joint jurisdiction. So particular thanks

to Dr. Nelson for chairing this review and this

subcommittee. In our opinion, the process went as

we had hoped it would, with a very smooth review,

but probably more importantly, a thorough review

and a recommendation that we feel is a good

recommendation coming to this Advisory Committee

for your final review and hopefully approval.

The review was done in a timely manner,

and that was a challenge considering that this is a

new committee, a new subcommittee, but it was done

in a timely way. And I think it was done with an

appropriate cast of experts. So we\'re very pleased

with this process and, Dr. Chesney, with your

permission, we\'re hoping that in those cases where

we have joint jurisdiction over a protocol in the

future that we\'ll be able to bring it back and

handle it this way.

So thank you very much.

DR. CHESNEY: Thank you for your comments,

and maybe you could stay here just for a moment,

43

and we\'ll ask now for any questions of the new

committee members for either Dr. Goldkind, Dr.

Nelson, or Dr. Schwetz.

Dr. Maldonado?

DR. MALDONADO: I just have a quick

question. Dr Nelson, I see that on page 1 you made

the statement\--and I basically also agree that you

did a great job with this review. You listed the

minor increase over minimal risk, which I agree are

just a minor increase. But then on page 2, you

gave a\--maybe I am just overreading this, but the

subcommittee strongly encourages the investigators

to narrow the age. I know you focused on that, and

I may have missed it. My understanding is this is

a single-dose study. I don\'t know what the

concerns will be with single-dose for neurodevelopmental

stages with a single dose, low dose.

DR. NELSON: The issue is not the impact

of that dose. There might be a response difference

that you could see, but the question is teasing

apart\--there is a debate on previous studies that

have been done of structural MRI scans, and there

44

are actually two previous studies of functional MRI

scans where the question is whether or not some of

the differences that may be seen are not related to

any underlying biological differences, neurodevelopmental

differences, but, in fact, the kids

with ADHD had been chronically exposed to a

medication which\--I\'m not a neuroscientist. I

guess I would characterize it as whether it\'s

created some element of remodeling of those

systems. And so try and eliminate that confounder,

the feeling was if they would narrow the age range

and then try to either get treatment-naive, which

may be difficult, or at least treatment-uniform at

lower doses which would give you hopefully a lower

duration of exposure, that you might be able to

begin to tease apart those two issues. That was

the scientific discussion among the experts.

DR. CHESNEY: Yes, Dr. Fant?

DR. FANT: Yes, this question may be a bit

naive, but it quickly comes to mind, especially

from the standpoint of taking the kids off the meds

for a couple of days and trying to ensure treatment

45

naivete and the question that that may have on

their response.

And so the question is: Are there any

over-the-counter stimulants or food additives that

could potentially interact with their response and

somehow muddy the data? And if so, is that being

controlled for or addressed in the protocol?

DR. NELSON: The answer is yes. I mean,

one of the discussions, of course, by the IRB was

whether caffeine and the element of caffeine

consumption could be used as a judgment. So there

are some confounders and the need to collect that

data, and it would be sort of self-defeating if

over the weekend you take the kid off of his

medication and then he drinks, you know, a couple

of cases of Jolt Cola\--which I don\'t even know if

it\'s still made or not. I have no stock in that

company. No conflict of interest on that

recommendation. Or Mountain Dew. I think Mountain

Dew has a lot of caffeine in it. So, yes, they

need to pay attention to that.

DR. FANT: And even with adolescents who

46

may be concerned about weight and appearance and

that sort of thing, some of the additives that are

contained in supplements in GNC at the mall, you

know.

DR. NELSON: Right.

DR. MURPHY: So, Dr. Fant, was that a

question or just a recommendation, I guess is what

I\--

DR. FANT: Well, it\'s a concern because if

we\'re talking about giving a drug to, quote, normal

kids, you really want to ensure that the data is as

clean, as interpretable as possible. You wouldn\'t

want to muddy the waters on something that could

have easily been avoided.

DR. MURPHY: I think that, you know, if

there are recommendations that this committee would

like to make, that\'s appropriate. And we wanted to

make sure that that was\--

DR. NELSON: I see that as just a

refinement of the recommendation to make sure your

subject populations are as uniform as possible. So

it\'s certainly consistent with our direction.

47

DR. CHESNEY: But we maybe should add a

sentence or two, Skip, just to\--I thought that was

an excellent point if somebody does\--I don\'t know

how long those stay in the bloodstream, but if

that\'s their breakfast and then they show up for

the fMRI, there may be a confounding variable.

Yes, Dr. O\'Fallon?

DR. O\'FALLON: Did you recommend that they

collect that information?

DR. NELSON: No, but we can add a sentence

to that.

DR. O\'FALLON: Okay. I think it would be

helpful to make sure that they elicit that

information.

DR. CHESNEY: Deborah, you were next.

MS. DOKKEN: I first want to compliment

Dr. Nelson\'s subcommittee. I mean, not only did

you do a thorough job, but I could fully understand

what you were talking about, and I was glad that

you included the issue of compensation and the

potential pressure on the twins in the assent

process.

48

I was also glad that at least in some way

you directed attention to the permission and assent

forms and talking about the chronology of the

procedures. But I had a further question about

those forms, which, frankly, I don\'t know what

their rating is in terms of reading level, et

cetera. But they certainly to me were not easy to

read and, in fact, were mixed. Sometimes they used

almost simplistic language; then you know, the next

sentence\--did you talk at all about just the forms

themselves and the language beyond the chronology

issue?

DR. NELSON: Yes, we did. But that\'s just

captured on page 5 under age where we just say

there\'s technical language would is not explained

in lay terminology.

I think two points on the process: A,

this still then needs to go back through the NIMH

IRB, plus it has two offices, not just one now,

that will recognize that for this to be finally

approved would require that kind of changes in the

documents. And I\'m absolutely confident that with

49

OHRP and FDA\'s involvement in making sure that

these requirements happen is that they will be in

more understandable language.

My own philosophy is there\'s no reason for

us to sort of nickel-and-dime the actual text, but

that was discussed.

DR. CHESNEY: Could I just add, there was

a great deal of discussion about the protocol and

about the consent form, and, in fact, one of the

committee members asked if this was a draft of the

consent form. And the folk from the NIMH

apologized and they said that they got so busy

addressing the issue of whether this would have to

come to a subcommittee that they hadn\'t really paid

that much attention to the consent form, but that

they would do that.

Dr. Newman?

DR. NEWMAN: I also want to compliment the

committee on a really very impressive, thorough

review. And I have three points. One is just a

clarification.

Looking on page 7, comparing Parts a) and

50

b), under\--I\'m just trying to figure out how\--I

have reservations about the value of the research

to kids with ADHD. I really\--it\'s very hard for me

to picture how this research will be useful, but

maybe that\'s just due to my limited scientific

knowledge. It says under C, the procedure is

likely to yield generalizable knowledge about the

subjects\' disorder or condition, which is vital

importance for the understanding or amelioration.

And I really couldn\'t go along with this being of

vital importance. But then under B it says it

presents a reasonable opportunity to further the

understanding, and I could go along with that. So

I\'m not clear on which of these two is the standard

that this research has to pass.

DR. NELSON: You point out an interesting

ambiguity in the regulatory language for which

there is no specific guidance about how one

interprets \"vital importance\" or \"reasonable

opportunity.\" My own view is that it needs to meet

both, that you would not want reasonable

opportunity to be a lower standard. And the issue

51

of vital importance is fundamentally subjective.

And from that standpoint, there was a recognition\--and

that\'s why I put earlier on the notion that

more speculatively. I mean, this is what\--I would

characterize this as sort of a basic science

question about the response and the neurodevelopmental sort

of receptor physiology.

If, in fact, there is no difference, it

would have an impact significantly on the

understanding of ADHD, and if there is a

difference, it would impact significantly, and then

might, not in this protocol but down the line,

potentially drive diagnostic and therapeutic

differences. One thing I learned is there are

individuals who are touting different structural

scanning tools for diagnosis of kids with ADHD, et

cetera, that many felt, in fact, were not evidence-based.

And so after hearing that discussion, the

subcommittee members felt that it did meet the

regulatory standard both for vital importance and

reasonable opportunity.

There was no, if you will, easily defined

52

paradigm for that.

DR. NEWMAN: Okay. Well, that sort of

leaves me uncertain. Let me go to my next

question, which was in the consent form they

specifically addressed the issue of potential

adverse effects of the MRI in terms of identifying

some little something which then people go, oh, we

wonder what this is, maybe you should go have that

checked out, but that not being covered by the

research study and the family may or may not have

medical insurance to cover that. And I believe

that\'s more than minimal risk. That\'s something

well beyond the range of what people experience

every day, the possibility of having some brain

abnormality uncovered, which then you have to

figure out how to deal with. So I wonder why that

wasn\'t considered, you know\--

DR. NELSON: It was. I didn\'t include it

in here because the data actually is that out of

3,000 scans, they\'ve only found four abnormalities.

And of those four, two were benign cysts and two

were actually early diagnosis of tumors where the

53

child benefited from that. So there was a

discussion in the subcommittee about the

implications of using a screening test in a

population that\--you know, being a statistician,

you can understand the sensitivity and specificity

issues. But after that discussion and the fact

that it\'s being conducted\--it\'s not a diagnostic

reading of the functional MRI. It\'s a separate

diagnostic MRI scan that, after hearing the

discussion, we felt that it was appropriate to

consider that under that category.

So they have enough data, I think, to sort

of\--at least reassure me that they\'re not going to

be turning up a lot of things that end up with

unnecessary testing.

DR. NEWMAN: If I were a parent trying to

make an informed decision about participating in

the study, those data would be very helpful to me

to know what\--to say this may happen, but they

don\'t give any numbers on how likely it is to

happen and what might be found. And so, you know,

I just think it\'s hard to ask someone to consent to

54

something, you tell them that risk, but you don\'t

tell them how big it is. So I think that would be

helpful for them.

And my last question was just about the

financial compensation. For the controls, you

know, it sounds like this may take several hours

out of the parent\'s day, and so, you know, having

tried to get people to enroll in studies before,

you know, I don\'t know whether there have been

pretests or what it would take. But if you\'re

going to ask someone to bring their normal child in

and get a lot of stuff done, you know, to me I

think maybe \$100 or \$110 split between parent and

child might not be enough to get people to want to

enroll.

DR. NELSON: No, it was not split between

parent and child. That would be wages for the

child, and the investigator actually said\--and this

did influence the committee\--that she did not

anticipate any problem with enrollment even if the

compensation and stipend was zero. I\'m just

telling you, that\'s what she said.

55

DR. CHESNEY: Could I just also comment

for Dr. Newman? It was suggested that they publish

the fact that they had only four abnormal MRIs out

of 3,000, which is certainly not within the realm

of most of our experience where MRIs show you all

kinds of things that you don\'t want to know. So

that suggestion was made.

We had a lot of discussion about the

science because it\'s a very\--to me it was a very

complex study to understand, and a lot of it was

based on the study by Viga (ph) et all that was

published in \'98 or \'99. And I thought\--it wasn\'t

until the very\--long into the meeting that Dr.

White, who\'s a child psychiatrist with a lot of

familiarity with functional MRI scanning, pointed

out the importance difference with respect to the

performance task in this study as compared to the

one published in \'98 or \'99, which had led to

perhaps some erroneous conclusions.

So I think that after a lot of discussion

we finally became convinced that the science was

important, if that\'s of any help.

56

Any other questions or comments? Dr.

O\'Fallon?

DR. O\'FALLON: I was just wondering about

the pregnancy exclusion. I didn\'t look at the

consent form closely enough to see. Presumably

they are excluding on the basis of pregnancy. Is

that it?

DR. NELSON: They are. It wasn\'t very

well described in the consent form, which was our

point.

DR. O\'FALLON: Okay. Well, but that\'s the

point. So they have to\--so they do have to take

this\--they have to have a pregnancy test. Now, I\'m

just curious. How do they think they\'re going to\--I mean,

how do they plan to deal with exclusion

basically on pregnancy alone when they don\'t\--they

can\'t tell it to the parent?

DR. NELSON: They didn\'t outline that,

but, I mean, I\'m confident that they can come up

with a procedure. We\'re just asking them to do

that, and I\'m sure OHRP will make sure it\'s a good

one.

57

DR. O\'FALLON: Okay. I wonder how they

are going to do it.

DR. CHESNEY: Very important points.

Any other\--Dr. Newman?

DR. NEWMAN: Let me just explain what my

reservations are about the value of the research,

and maybe you can reassure me. It seems to me that

ADD is a clinical diagnosis, and in making the

diagnosis, one of the main decisions that you\'re

trying to guide is whether to begin stimulant

medication. And if you begin stimulant medication,

you want to see whether it helps the child and

monitor that and discontinue it if it\'s not working

and continue it if it is.

And I just cannot visualize how an MRI

scan would ever sufficiently predict a child\'s

response to medication to be clinically useful,

because, I mean, they may well find some

statistically significant differences where the

something or other is, you know, a half a standard

deviation different in one group than the other, or

maybe they\'re quite different. But the fact is

58

whatever they find, the question is really whether

this child would benefit from treatment or not.

And, you know, the way you determine that is

whether\--either trying the treatment and seeing if

it helps, or if you were going to do a study to see

whether imaging helps, you would see whether

imaging predicts response to treatment, not whether

imaging predicts or is associated with someone

having received this clinical diagnosis.

So I am a little bit worried if it does

show a difference that this will spawn a whole

imaging industry of people wanting to get their

children\'s heads scanned to see whether they really

have it or not, which I think would just be going

in the wrong direction.

DR. NELSON: I guess two comments. This

has nothing to do with the clinical response of the

children. There is no benefit. It has nothing to

do with that. Whether or not it\--if it does show a

difference, appropriately designed, it would spawn

a functional MRI industry I think is speculative

and, in fact, is explicitly, if you at Subpart A,

59

excluded from what an IRB ought to consider. The

long-term policy implications of research is not

something that IRBs are supposed to consider, and I

wouldn\'t necessarily import it under vital

importance.

The question is whether or not there are

structural or functional differences, and

presumably based on receptor density, et cetera\--it\'s not my

area so I\'m just saying things that you

could have read in the protocol and listening to

the scientists. And as a basic science question, I

think that\'s an important one. And how it might

then impact down the road in terms of understanding

whether there\'s a differential or similar response

to stimulants, I mean, the literature is quite

mixed in terms of reading some of the background

material in the protocol.

So there is no connection in doing this

with determining why they might respond clinically.

There is no\--and, in fact, many of our recommendations were

meant to prevent that confusion

from being in the minds of the participants by

60

removing any semblance of benefit from the sort of

surrounding aspects of the science. But, you know,

I think ADHD is a controversial area, and it\'s

partly why we felt this needed to be looked at

carefully and then done well, because I think the

positive or negative results could have an impact

in different directions.

DR. CHESNEY: I think Skip expressed it

very well. The purpose of the study was not to

have any clinical diagnostic value or clinical

implications. The purpose of the study is really

to understand, as Skip said, the neurophysiology

and neurochemistry\--to try to understand the

neurophysiology and neurochemistry of ADHD better,

and because of the twin aspect, to see if there are

any genetic aspects.

Dr. Maldonado?

DR. MALDONADO: A quick question that goes

beyond this study, but it\'s in the context of ADHD.

One of the premises that I think a lot of

researchers\' work is under that if the studies can

be done in adults, don\'t do it in children. And

61

now adults are being diagnosed with ADHD. Has

something similar been done in adults or can be

done in adults, you know, consenting adults, so you

don\'t use this area of consent of children?

DR. NELSON: Two points. That specific

question was raised by the subcommittee. There

have been similar but not identical studies, but

it\'s clear that the adults are different in this

regard and that the information that you would get

would be of no use to this issue. And that

discussion actually is why you may even\--in the

discussion it was clear that the scientific

arguments might push you in the direction of using

actually the 9 to 12 age group as opposed to the

older age group because there may even be those

kinds of adult changes when you get into sort of

late adolescence. But we felt that that was not

clear enough that we would make a stipulation as

opposed to recommendation.

So I think that is an important principle,

and it was asked and answered in the negative, that

adult information here would be of no use to

62

answering this question.

DR. CHESNEY: Dr. Schwetz, did you have

any additional comments about the questions from

the committee?

DR. SCHWETZ: No, I don\'t have anything

else to add. Thank you.

DR. CHESNEY: Dr. O\'Fallon, you look like

you were\--

DR. O\'FALLON: I hesitated simply because\--but I\'m

a mother and not an M.D. I\'ve had an MRI.

I don\'t know what\--for my neck. I was wondering

what a functional MRI for the brain involves for

the child.

DR. NELSON: Nothing different than an MRI

scan.

DR. O\'FALLON: But the question is they

are enclosed, so there is the issue of

claustrophobia?

DR. NELSON: Correct, but they have

screening procedures for that. There\'s no issue in

that. The kids are actually less claustrophobic

than the adults.

63

DR. MURPHY: Skip, why don\'t you describe

the screening procedure\--

DR. NELSON: They have a training MRI scan

which is\--and they make\--you know, first they\'ve

got to make sure the kids can do these tasks, so

they use the stop task and a training MRI scan.

They have a whole sort of session. I mean,

everybody\--if a kid doesn\'t want to do it, then

that\'s the end of it. You know, their procedures

are excellent with respect to that. The issue is

not that they\'re not doing it. The issue is they

just didn\'t describe it in the protocol. They

described it quite completely in the discussion on

Friday.

DR. MURPHY: I think as a risk what you\'re

trying to get at is that those kids that are going

to have that impact of anxiety, psychological fear,

will be\--will not be enrolled. In other words,

that\'s where the screening procedure would help

select those children out.

DR. O\'FALLON: Yes, but, of course, the

screening itself could cause this\--I mean, they

64

could precipitate this anxiety. I don\'t know what\--at the

time of my MRI, I was told that there\'s a

fairly high percentage, like 25 percent of adults,

anyway, that experience\--well, that\'s what I was

told, when I was told about it, that experience

claustrophobia.

DR. GOLDKIND: Could I speak to that?

They actually show the kids a video, and they have

a very well organized approach, even before they do

the screening program that was described to us on

Friday. Additionally, they said that because

children are smaller than adults physically, they

are not as confined. They don\'t have the feeling

of claustrophobia that adults do based on physical

size and also based on psychological orientation.

Generally speaking, children don\'t have as high a

claustrophobia rate as adults do.

So for all those reasons, the subcommittee

felt that it was a minimal risk intervention. And

then as Dr. Murphy said, if a children demonstrates

hesitation at any step along the way prior to

getting to the actual enrollment, they\'re excluded.

65

DR. NELSON: Twenty-five percent sounds

quite high to me, anyway, even for adults.

DR. O\'FALLON: Maybe it\'s because of the

practice of ours. We have a whole lot.

DR. CHESNEY: Let me ask, not seeing any

further hands being raised, does the committee feel

that they are comfortable endorsing this summary of

the events of Friday? We\'re not required to take a

vote on this. Unless there is somebody who is not

comfortable endorsing this, we would like to pass

on to Dr. Murphy the committee\'s endorsement.

\[No response.\]

DR. CHESNEY: Not seeing any hands being

raised, I think that we can\--yes, Dr. Nelson?

DR. NELSON: I just want to ask, you know,

in terms of adding the issue of collecting data and

trying to exclude caffeine and other stimulants

under the design recommendation and the discussion

of the communication of the risk of inadvertent

findings on the diagnostic MRI scan, can that just

be made by office staff? Or do you want me to just

do it myself and give it to you?

66

DR. JOHANNESSEN: We can do that.

DR. NELSON: Okay.

DR. CHESNEY: Thank you very much, Dr.

Nelson, for chairing this\--

DR. MURPHY: We have one more question

over here. Would you like to please identify

yourself for the committee and ask them this

question?

DR. STITH-COLEMAN: My name is Irene

Stith-Coleman from OHRP. What I would suggest is

that if\--in terms of the additional statement,

could you clarify if you recommend that it be a

recommendation or stipulation? That would be of

help to OHRP.

DR. NELSON: The first one about caffeine

or other stimulations is going to go under the

design recommendation, not stipulation. And then

the comment about communication of risk, one of our

discussions at the meeting was whether they, you

know, have all the data, but I think the

recommendation that they communicate that

information in a meaningful fashion to parents

67

would go under the diagnostic MRI scan, which fits

under a stipulation. The only thing that\'s a

recommendation to consider, which they could then

come back with arguments for or against, is number

3\. Everything else is stipulations.

DR. MURPHY: That was helpful. Thank you.

This is a new process. As Dr. Schwetz said, we\'re

very enthusiastic about the fact that we aren\'t

setting up a process that would almost engender or

increase the possibility of having differing

recommendations if you empanel two different groups

and have two different sets of experts. There\'s

always a probability that you going to get two

different sets of answers. So I think that\--however, it\'s

been very helpful to hear the

comments from this group, and I think that at this

point, Dr. Schwetz, what we need to make a cut on

is where recommendations would just go straight up

forward via both of these mechanisms versus if

there were some major concerns, what we would do in

that situation. I think we\'re not at that level

right now, but that is certainly something we would

68

want to consider for the future.

Skip?

DR. NELSON: Just one other point that I

think, as word goes out, might be surprising to

many IRBs, although I realize that it\'s, in fact,

the correct interpretation of the regulations, many

IRBs do not think simply because you\'re using an

FDA-regulated product in a clinical investigation

or in the research that it\'s an FDA\--that the FDA

has oversight. You know, both of these products

are being used in accord with clinical

recommendations at doses that are being done

clinically. And I think that to many IRBs might be

a surprise. So just to alert you to that as this

word might trickle out. I do know that the FDA

does have jurisdiction, even if it\'s an approved

drug being used in a clinical investigation. But

many IRBs don\'t think that\--or don\'t know that, I

should say.

DR. MURPHY: And it\'s new for the agency,

so actually it\'s something that we are making sure

everyone within the FDA is aware of also. So I\'ll

69

just give you that sort of forewarning.

DR. CHESNEY: Thank you very, very much to

everybody who prepared for Friday\'s presentations

and for the process, Dr. Nelson for chairing it

all, and Dr. Schwetz and the other members of the

OHRP who were there, but who also took the time to

come today. We very much appreciate your time.

And thank you to the committee for your questions.

They were very, very perceptive given that you

hadn\'t been at the meeting Friday. You really

raised some very important and additional issues.

I think I will move on to\--

DR. MURPHY: I just have one last person I

wanted to thank, and that\'s Terry Crezenzi (ph) and

Sara Goldkind, working with OHRP, spent many, many,

many weeks and months putting this process

together, and just because she made the terrible

decision to leave us and go on detail elsewhere, I

wanted to make sure we recognize the contributions

that she has made to this process.

Thank you.

DR. CHESNEY: Thank you. We don\'t know

70

about all the behind-the-scenes work, so thank you

very much for clarifying that.

All right. Well, moving on to the next

section of today\'s meeting, let me introduce Dr.

Solomon Iyasu, who is a pediatrician and medical

epidemiologist. He was with the CDC for 13 years

leading the Infant Health Program there. And here

at the FDA, he\'s a medical team leader in the

Division of Pediatric Drug Development and a

medical epidemiologist in the Office of Pediatric

Therapeutics. I don\'t know how you all keep track

of who you are.

Today\'s talk will provide an overview of

the BPCA mandate for adverse event reporting, the

review process, and FDA\'s adverse event reporting

system. Dr. Iyasu?

DR. IYASU: Good morning. It\'s a pleasure

to be here and present to you the adverse event

report for several products that have been given

pediatric exclusivity.

The Best Pharmaceuticals Act for Children,

which was enacted in 2002, does have a provision

71

for mandatory reporting of adverse events for

products that have been given exclusivity. Under

Section 17 of that act, FDA is required to review

adverse event reports during the first one year

after exclusivity is granted to a particular

product. And once that review is done, then the

FDA will report a summary to the Advisory

Subcommittee, which now is a full committee, for

their review and recommendations.

The review process that we have

implemented at FDA for drug products includes a

very close collaboration between the Office of Drug

Safety, which does the primary review of the

adverse events reported for the one-year period,

and then also the Division of Pediatric Drug

Development, who would be participating in this

review, and then finally the Office of Pediatric

Therapeutics, which is the new office which has

overall responsibility over adverse event reporting

for pediatric issues.

Just to outline to you what we\'ve been

doing over the last two years in terms of the

72

review process, we have implemented sort of a

process which includes and defines responsibilities

for each of the participating offices. The Office

of Drug Safety has responsibility for reviewing the

adverse events reported during the one year and

also has responsibility for immediately discussing

any serious unexpected events including deaths with

the Office of Pediatric Therapeutics and also the

Office of Counterterrorism. And, finally, it has a

responsibility also for submitting the written

safety review and sharing them with OCTAP, which is

the pediatric group, and the Office of Pediatric

Therapeutics, and, more importantly, with the

review divisions that are responsible for these

particular drug products.

Then OCTAP, which is Office of

Counterterrorism and Pediatric Drug Development,

and OPT have joint responsibilities for also

notifying the Office of Drug Safety once

exclusivity determination is done for any products,

so that the tracking could start then for a period

of one year after that date of determination.

73

The medical officers within these two

office also have roles in reviewing the ODS reports

that are submitted, and then also looking at the

individual adverse event reports, the MedWatch

reports, and also preparing summaries and

presentations for this committee.

We try as much as possible to focus the

adverse event presentations on issues, safety

issues that may have arisen during the review

process so that the committee\'s time is better

spent on important issues.

We have also developed, in collaboration

with the Office of Drug Safety, a template for

summarizing the review, and the safety review

includes an executive summary that sort of

highlights what the issues are from the review. We

also include in that template a review of the

adverse event reports for adults and pediatric

patients from the original drug approval date up to

the time that the drug has been reviewed for the

exclusivity process. So it\'s a longer view, but

it\'s an overview, really, trying to see what the

74

number of reports have been for adults and in

pediatrics, and also trying to get a handle on

whether\--how many of them were actually U.S. origin

and how many of them are actually foreign reports.

Then for the more focused pediatric

review, we have a detailed template which I\'m

highlighting here were the issues of the specific

reviews that are done by the Office of Drug Safety.

We expect counts and labeling studies of the top 20

most frequently reported adverse events within the

pediatric population as well as adults, but we

focus more on the pediatric issues. We also try to

get from the MedWatch reports the summaries of the

demographics, age, gender, distribution of the

adverse event reports for the one-year period,

including a description of the serious outcomes,

indications, and doses that may have been

associated with these adverse events.

Then there is an evaluation of whether

these adverse events reported during the one-year

period are unexpected events or are they unique to

pediatric patients and not reported in adults. So

75

there\'s an evaluation that\'s done sort of comparing

adult and pediatric reports.

Also, an evaluation of whether there is an

increased frequency of non-pediatric adverse events

in this population, but this is done for the one-year

period. And then, finally, sort of developing

adverse event profile for that particular drug

product, which will then sort of highlight what the

issue is, if there is an issue that has developed

during that review process.

We also have for the denominator data,

trying to understand what the exposure us in the

pediatric population, we use various databases that

are available to FDA, which I\'ll briefly describe

later on, which estimate drug use in the outpatient

setting for this drug product, as well as for the

inpatient population.

The role of the Pediatric Advisory

Committee is really to assess and discuss the

presented adverse events. We\'ve been doing this

now for almost two years. And if appropriate,

recommend additional pediatric review and/or any

76

regulatory action if deemed appropriate.

T2A The role is evolving. This is a new

committee, and there may be other responsibilities

or even roles that would be defined as we go into

having more experience with this process.

Now, I want to sort of give you a brief

overview, top-line view of what the adverse event

or the Postmarketing Drug Surveillance Program

includes and the various components that may be

tapped to assess drug safety. The cornerstone

about this is, of course, the passive surveillance

system, which you\'ve heard about so much in

previous presentations, which is the Adverse Event

Reporting System, which includes adverse event

reports, spontaneous reports, and manufacturer

reports that are sent to FDA.

I also mentioned sort of the\--on the

denominator side sort of trying to assess exposure,

the drug utilization databases that FDA has access

to, which include outpatient, inpatient, and some

longitudinal data.

Other databases that may be tapped also

77

for evaluation of adverse events, external health

care databases which may includes claims databases

from special populations or from the general

population, and then there is also information sort

of a repository of background incidence rates on

different adverse events or conditions that may

come from hospital discharge surveys or from the

literature that we may actually tap in our

evaluation.

Then, finally, there are some active

surveillance systems that look into possible drug-associated

adverse events. I\'m not going to go

into detail about this, but the DAWN is the Drug

Abuse Warning Network, and then NEISS is the

National Electronic Injury Surveillance System,

which is run by CDC, and TESS is the Toxic Exposure

Surveillance System, which is run out of the Poison

Control Centers.

Now, just to give you an overview of the

most pertinent one, which is the AERS database, as

some of you probably know. It originated in 1969

as the Safety Reporting System. It currently

78

contains more than two million adverse event

reports in the database, contains drug and

\"therapeutic\" biologic adverse event reports, with

the exception of vaccines which has a separate

reporting surveillance system.

Just to give you some idea of what reports

are, they are mostly voluntary/spontaneous reports

that may come from health care professionals,

consumers, patients, or others. But also a large

majority of them are actually mandatory reports

that come from manufacturers required for

postmarketing reporting purposes by law. All

adverse drug experience information obtained or

otherwise received from any source, foreign or

domestic, will be included in this. And to give

you more detail, there will be more detailed

discussion later on about this.

But in 1993, the whole Adverse Event

Reporting System was redesigned and the MedWatch

form was developed. You probably can\'t see this

slide, but in your handout you probably can

identify some of the design aspects of the MedWatch

79

system. But, in short, this is the form that

unifies in terms of reporting for drugs and also

for biologic products and also for devices and

dietary supplements.

Now, by law there are definitions for

different kinds of reports. What manufacturers

must report is defined under 21 CFR 314 that

includes all adverse event reports from commercial

marketing experience, postmarketing studies, and

scientific literature. And this may include all

domestic spontaneous reports that must be reported

to the FDA. In terms of foreign or literature

reports, all serious, unlabeled events are

mandatory in terms of reporting. And it may

include also study reports which may be serious,

unlabeled, or any adverse event with a reasonable

possibility that the event may be related to a drug

product.

Adverse drug experience is also defined by

the regs. Any adverse event associated with the

use of a drug, whether or not considered drug-related\--this

is an important point\--has to be

80

reported. This may include accidental or

intentional overdose or occurring from abuse or

drug withdrawal or failure of expected

pharmacological action.

Now, I mentioned before the serious

adverse events, and there is a regulatory

definition as well for this: any event occurring

at any dose that results in any of the following

outcomes. And this has been mentioned several

times in yesterday\'s presentation. Some of you

were not there, but this may include deaths or

life-threatening adverse events or something that

results in hospitalization or prolongation of

hospitalization or persistent/significant

disability or may result in a potential congenital

anomaly or birth defect or requiring intervention

because of an adverse event associated with a drug.

Also, there\'s a definition also according

to the regs for unexpected adverse drug events or

experience: any event not listed in the current

labeling of the drug product, including events that

may be symptomatically and pathophysiologically

81

related to a labeled event, but differ because of

greater severity or specificity. So examples may

be like hepatic necrosis versus hepatitis. So

there is a regulatory definition as well for those.

Now, just to briefly go over the strengths

of the AERS system, it includes all U.S.-marketed

drug products. It\'s simple because it\'s passive

surveillance. It\'s less expensive than having an

active surveillance system, which may be very

expensive. It provides for early detection of

safety signals, and especially good for rare

adverse events.

There are some very significant

limitations of the AERS system. Underreporting is

a serious problem, but this varies from drug to

drug and also over time. Reporting may be more

during the early phases of the marketing and may

taper off later on. If there is media attention or

public attention on a particular safety issue,

reports may go up. Or it depends on what kind of

drug it is, whether it\'s OTC or prescription drug.

You may not get as many reports for OTCs and so on.

82

So there is a problem with underreporting.

Then there are also issues about quality

and completeness of reports. That also varies, it

often may be poor. You may not get information

maybe that would help you assess temporality of the

drug exposure with the event. You may not get

information on concomitant medications or may not

get very good medical history of the patient from

whom the adverse event is being reported. So that

is an issue which is sort of common to all passive

surveillance programs.

Another important aspect in terms of

limitations, the limited ability of the system to

really estimate, help estimate true adverse event

risk rate because the numerator is uncertain

because of underreporting, which I mentioned, and

also the denominator must be estimated or it\'s

projected from sort of drug use databases that we

have, virtually\--may be difficult for some

inpatient or OTC drugs.

I\'ll just briefly go over the outpatient

drug use. I\'m doing this for the benefit of the

83

new members to sort of give you what the sources

are. For outpatient drug use, we mainly tap into

the IMS Health System. One database is National

Prescription AuditPlus, which provides an estimate

of the number of prescriptions from retail

pharmacies. The point on this limitation is that

it does not include information on gender or race

or age. So the information is limited, but it can

give you an estimate of what the outpatient

prescription volume is.

The other database, which is also an IMS

Health product, is the National Disease and

Therapeutic Index, which is a survey of 2,000 to

3,000 office-based physicians and really measures

mentions of drugs during that encounter and

includes a variety of specialties. But one

disadvantage is that the diagnosis cannot be linked

to the drug use. And the projections may be

unstable, especially when use is very limited in

some pediatric\--for some drugs in the pediatric

population.

Another source for outpatient drug use is

84

the National Sales Perspectives, which is also an

IMS product. This is really a measure of the

volume of drugs that are sold from the

manufacturers to various distribution channels.

This may include retail outlets and non-retail

outlets. This is sort of a surrogate for use if

you see that what is actually moving to the retail

pharmacies or channels is really representing what

is actually being used by patients. But also an

important limitation is that we don\'t have

information on age and gender in this database, so

we\'re not able to be more specific.

For inpatient drug use, we have several

databases. One is AdvancePCS, which is based on a

large prescription claims database of the insured

population. That includes about 75 million

patients. But we don\'t have a projection

methodology to sort of estimate it on a national

level.

Premier is another database which comes

from approximately 450 acute, short-stay, non-federal

hospitals. The projection methodology is

85

available. It may not be very good for some drugs,

so it is selectively appropriate in terms of making

national projections. Again, the estimates cannot

be linked to diagnosis or any procedure, and

importantly, it misses the drugs that may be

administered at the hospital outpatient clinics,

especially come to mind oncologic drug products.

The last database that we have utilized is

Child Health Corporation of America, which includes

really just pediatric hospitals, and the data come

from about 29 free-standing children\'s hospitals

distributed around the country. An important

limitation is that this is\--we don\'t have a

projection methodology to estimate at a national

level, so whatever we get in terms of this

database, although it may be specific to the

pediatric population, is not representative of what

the national experience may be.

Now, having gone over this overview, I

just wanted to touch upon the drug products that

we\'ve reported on under the mandated BPCA review

process. We started our first presentation in June

86

2003, and we covered several products at that time.

The second one was October, the third one was

February, and then June. So we\'ve had four major

adverse event reporting that we\'ve done for over

maybe 22 products, and today\'s presentations will

be an extension of that.

Just to give you examples of some of the

outcomes of the prior Pediatric Advisory

Subcommittee meetings, we\'ve discussed very

important issues including SSRIs and SNRIs in

relation to suicidal behavior and then class

labeling for neonatal withdrawal, again, with SSRI

products. That was actually a subject of

discussion in the last AC meeting, subcommittee

meeting. And then we have also discussed the

fentanyl transdermal products, which have been

associated with inappropriate use that may have

resulted in some pediatric deaths, and there were

some specific recommendations that were provided by

the subcommittee for FDA regarding these drug

products. So the mandated adverse event reporting

has had important implications in terms of focusing

87

our attention on some of the safety issues.

Despite its limitation of being just for one year,

it\'s really brought attention to looking at safety

issues in the pediatric population.

Now, just to give you an overview of what

is going to happen today the way it\'s laid out, we

are going to have presentations on several drug

products, as you can see in the agenda. Dr. Hari

Sachs is going to be presenting the one-year

adverse event reports for ofloxacin, and

alendronate, and Dr. Susan McCune will be presented

on adverse events regarding fludarabine, and Dr.

Jane Filie will be presenting on desloratadine.

And then we\'ll have a break, and in the next

section we will have several presentations which I

will introduce later in more detail, but we have

adverse event reports for fluticasone- or

budesonide-containing drug products. And there

will be a one-hour slot for this presentation. In

regard to the drug products containing fluticasone,

we\'ll be addressing that.

There is also a question that we have for

88

you to consider, so I wanted you to think about

this while the presentations are going on. We\'ll

ask you this question, and then we\'ll be very

looking forward to your recommendations regarding

these products.

DR. CHESNEY: Thank you very much. That

was extremely helpful to me, reviewing the

databases. You\'ve probably done that many times

before, and I didn\'t remember, but it\'s very, very

helpful.

Any questions from the committee? Yes,

Dr. Nelson?

DR. NELSON: I agree you\'ve taken a system

that doesn\'t provide a lot of data and tried to

make it as best as possible. I guess this is a

comment that perhaps at some future meeting we may

want to discuss what we could do in the future

perhaps to try and get a better handle on safety.

The reason I\'m concerned is if you think about the

expanse of the past two days, all of those drugs

were labeled for suicide as an adverse event, and

most individuals, apart from the signal that came

89

out of the requested exclusivity trials, would

think that, in fact, that\'s potentially unrelated

to the drug and related to the disease. And so

none of that data emerged out of this. What it

emerged out of is a review of the exclusivity

trials themselves.

And at some point, I think it would be

worth just discussing as a general topic, apart

from the\--you know, as we\'ve done on individual

agent can we do better than this system and what

would that look like. And I\'m not sure what the

answer would be in terms of that, but I\'m struck\--my

impression is that we wouldn\'t have seen the

signal that we saw that led to the past two-day

meeting using this system. And the only way that

came up was with the request to exclusivity

studies.

DR. IYASU: Yes, well, let me make a

comment. As you recall, since you\'ve been involved

in this committee a couple of years, we did a

report on suicidal ideation and also suicidal

behavior associated with drug products like

90

Citalopram and Paxil in the past. Now, we know the

limitations of the system in terms of trying to get

a handle on what the rates are or, you know, the

estimates of the risk on this adverse event.

Nevertheless, I think the AERS system, the best it

can do is that it can sort of identify some adverse

events that may not have been detected during the

clinical trial, but sometimes it\'s also possible

that if you see it in the clinical trial setting

and you see it also in the one-year post-exclusivity period,

then it sort of raises a

question.

So, actually, I want to go back to what

happened early last year when we were talking about

Paxil. The discussion of the clinical trial data

was done in conjunction with the adverse event

report, so it was supportive in the sense of us\--you know,

mandating us to look more carefully at

the clinical trial data because we were also seeing

these reports in the Adverse Event Reporting

System.

So I would say that the AERS system cannot

91

give you an estimate, but it can just focus you or

even help you look more closely at clinical trial

data if you do see these kind of events.

DR. MURPHY: Skip, I think what you\'re

bringing up is a really important question, and

actually, I was going to say this at the end of the

meeting, but after we do maybe one more meeting

with the new committee with this process, you will

see we have already internally decided\--and Dr.

Lumpkin is now my new boss, and we want to

internally review, including, you know, Office of

Drug Safety, New Drugs, and other Centers, have an

internal review of how to enhance the way we go

about the safety reporting, because it\'s very clear

to us that Congress wants us to be able to make

valid reviews, if you will. We\'re all telling you

there are problems with this system and we all

know, so how can we enhance it? And I think the

prior committee has seen that we\'ve gone from just

reporting AERS and what\'s in the label, to going

back to the actual original clinical trials,

looking at signals in those clinical trials and

92

trying to tell you what was seen then, what\'s seen

in AERS. So we really do agree that we need to try

to develop the most robust way of doing this.

Now, having sort of laid bare the fact

that we all think this is not the best system and

we want to make this a useful process, I will tell

you that just having the process has an impact that

you don\'t see. Okay? You know, having been

mandated and going to a division and saying this

product is coming up for review and we need\--it

means the divisions, ODS, everybody has to go back

and look at this material. And as Dr. Iyasu was

saying, Paxil was a\--I think we mentioned to you,

we delayed actually presenting that because of all

of the activity that was going on. And when we

looked at the AERS system, we saw some actual

concerning things. Now, we couldn\'t make any

attribution, but compared to the other products\--and you

have to do all those\--you know, the other

products weren\'t used as much, et cetera, there

still were some things that were concerning.

So I think we feel that the process, even

93

as it is right now, has served some useful

purposes, but that clearly we would like to enrich

it and make it more robust and make it more

scientifically useful for the committee to

understand, because, otherwise, what we\'re always

doing is putting pieces\--you know, we\'re taking

pieces of data and trying to make sense out of

these pieces of data.

So the intent is that we will be coming

back to you, and as I said, we\'ll see, you know,

how the next meeting or so goes, give the new

committee an opportunity to see this and provide us

additional\--and probably come to you as a complete

subject unto itself, a topic for the committee, how

to better do this process.

DR. NELSON: And just to\--my comments are

meant to be critical in the positive sense. The

progress since when I remember first hearing some

of this data two years ago has been phenomenal in

terms of what\'s been able to be accomplished with

all the warts and pimples of the existing data. So

just to say that.

94

DR. IYASU: Thank you. I appreciate the

comments, and we\'re always open to suggestions to

make it even better and make it more useful.

DR. CHESNEY: I think Dr. O\'Fallon and

then Dr. Ebert. No? Dr. Ebert.

DR. EBERT: This is somewhat related, and

I wonder whether the agency has considered this as

well. But a lot of what you\'ve focused on have

been, of course, adverse events that have happened.

But I\'m wondering whether there is also the

opportunity to screen for medication errors that

occur and whether that entire\--it may be a slightly

different database, whether that\'s through IMSP,

for example, and whether there may be systematic

errors that occur in treatment of pediatric

patients as opposed to adult patients, whether it\'s

product selection or selecting the wrong product

because it looks similar to another substance, for

example.

But it seems that there\'s obviously been

an increasing public outcry for making sure that

our medical practices are also safe in addition to

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these adverse effects that occur.

DR. IYASU: I think that\'s an important

point. Again, AERS has limitations in that area,

but, nevertheless, I recall in one of the

presentations we had an issue with medication error

involving two products, one was Zoloft and Zyrtec,

and that came out loud and clear, I think, in the

adverse event review, and there may be others also

that may be picked up. Yes, that\'s an important

issue.

DR. CHESNEY: Dr. Maldonado?

DR. MALDONADO: Yes, I have a couple of

questions of process or actually what you said that

one of your list of five items there was unique and

unexpected pediatric AEs, and I just kind of went

through some of the presentations. Is that data

going to be presented in a way that we can actually

see if there is excess pediatric risk in the use of

these drugs, an excess compared to adults?

Typically most of these drugs that are used in

adults tend to advertise more than in children, so

seeing a list of adverse events in children, maybe

96

because I\'m used to seeing it, without the context

of knowing is this an excess risk? Are children

suffering an excess risk of X adverse event? Or is

this just the background that you see in the use of

the drug? That\'s one thing. And I haven\'t seen

that in previous presentations.

And so I come out of the meetings, okay,

yes, I saw several adverse events and some of them

very horrible adverse events, but it doesn\'t give

me a sense is this something that is a red flag in

pediatrics that needs to be looked at more closely?

That\'s probably why Dr. Santana asked for the adult

data on SSRIs yesterday, and not so much to look at

the adult data but is an excess risk there in

children?

And the other thing, in your last slide

you said keep in mind the off-label use of

fluticasone. What exactly is it you want us to

focus on when the presentations come so we\'re alert

to that?

DR. IYASU: Are you talking about the

question?

97

DR. MALDONADO: Pardon me?

DR. IYASU: Are you talking about the

question?

DR. MALDONADO: Yes, the last slide. I

just don\'t know what you want us to focus on.

DR. IYASU: I think the focus would be for

you to consider the presentations regarding these

drug products, and there will be a series of them,

and then to get your input as to whether there is

any additional labeling concern or information that

you would like to include in the label, concern

about the drugs as\--the use of the drugs as labeled

currently. So there is a concern about that. Of

course, you have the label that is included. So

it\'s as labeled now, they have been used in

different ways, and is there any concern regarding

that.

DR. MURPHY: Sam, they\'re going to present

what they think the adverse event, if you will, is,

what they\'ve done to deal with it, what\'s in the

label now, and does the committee think that\'s

adequate. So it\'s really\--you\'re right. You don\'t

98

have any information to answer that question.

They\'re just trying to show you where they\'re going

with the information they\'re going to present.

DR. IYASU: The context for that question

will be clearer, I guess, once the presentations

are done. But to go back to your first question

about the unexpected\--or regarding whether adverse

events are occurring in excess in pediatrics as

opposed to adults, I think that\'s an important

question, and we haven\'t really done this for the

products. We do a top-line review for the one-year

period, and then most of the review has focused on

whether the same adverse events have also been

reported in adults. And we do sort of that kind of

comparison based on how frequently the adverse

event terms, as we call them, are reported.

When there is an issue that may be

considered to be critical, then we would like to do

sort of additional cultivations trying to see what

the background rates are, and then also look at

what the reporting rates are. We haven\'t done that

except, I guess, for SSRIs. But for other

99

products, that\'s something that can be done, but,

you know, you must know that there are a lot of

caveats in trying to come up with a reporting rate

or relative reporting rate for these drug products.

But when there is a need to do that, we will

actually do that.

DR. CHESNEY: Dr. Nelson has a question

for you.

DR. NELSON: Actually, just a comment on

that. Knowing the deficiencies of the system for

being able to get the denominator, it\'s not clear

to me that we necessarily need to look at the ADER

system in adults and compare them, and you\'re sort

of comparing information where you don\'t know the

denominator in either case.

If you\'re comparing it to the data that

obtain in clinical trials and look beyond just the

pediatric data in clinical trials to the adult data

in clinical trials and look at it in that context

and see if there\'s anything, it\'s different as a

signal for adults, probably that would be useful

data because then you can actually establish

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frequency for adults because we have a hard time

establishing frequency in pediatrics using this

data, which is the main problem with it.

So I wouldn\'t encourage you to try and do

the thing that we can\'t do in kids in adults, too,

but if the comparison is made with clinical trials

where you can have that denominator, then that

might\--then I think that would probably be useful

information.

DR. MALDONADO: I was referring actually\--I\'ve

seen some drugs presented that I\'m very

familiar with, and what I\'ve seen here presented,

it\'s not very dissimilar to what I see outside this

room, meaning that the same adverse events actually

in absolute numbers, much larger in adults. So my

question when I see those presentations here, is

this a signal in pediatrics? Should it be worried

to\--and I\'m not saying that we should look at the

data. I mean, I think they do a good, a much

better job looking at the data. That\'s what they

do for life. But it\'s to identify for us excess

risks, because those are the ones that you really

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have\--and I know it\'s difficult. I know it\'s

difficult. But just looking at that list without

the context, it leaves me like, yes, I\'m not

surprised that this is happening, this is happening

in adults 10 times more or 20 times more.

DR. IYASU: I think you make an important

point there, and we just have to live with the

limitations of the data. What we can do, when it\'s

an important issue, serious adverse event, we can

go out on a limb and go to other databases like

Claims database, which has its own set of

limitations and caveats. So there are many avenues

that you can go, but reporting rates or relative

reporting rates are the best that we can do with

this limited data set. We have refrained from

doing that because of the limitations in terms of

defining the actual numerator that you use, and

also the denominator, especially for pediatric. So

we may\--we\'re concerned about sending the wrong

signal as to the relative safety of certain drugs

if we don\'t have\--if we\'re dealing with uncertain

denominators and uncertain numerators. So that\'s

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where, I think, the problem is in trying to assess

it.

So what we\'ve done is if there is really

an issue, then our best resource is really the

clinical trial data. And what we\'ve done is the

initial sets of presentations that we\'ve done for

adverse events for these drugs did not include a

review of what was actually in the clinical trials

done for exclusivity. Now all our reviews include

summaries of the exclusivity trials and what kind

of safety signal this might have resulted that may

be similar or been supported by the adverse event

reports.

So we\'re trying to strike a balance here

and trying to give you the best information that we

have with all the limitations for interpretation.

So I can\'t say anything more than that. If there

are other suggestions from the committee, we\'ll be

very glad to consider them to improve the system.

Thank you.

DR. CHESNEY: I think it also doesn\'t

address the issue of the drugs that didn\'t go

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through exclusivity. But I think in your spare

time, if you could develop a national database that

would capture this inform for us.

\[Laughter.\]

DR. CHESNEY: Dr. O\'Fallon?

DR. O\'FALLON: This brings us back to the

problem\--clinical trials provides the very best

data we have, no question about it. You know, I\'m

a lover of clinical trials. But there\'s all those

comorbidities that are excluded that are

encountered, and a good chunk of the patient

population are excluded often from these clinical

trials. And so the question is: If there are a

lot of adverse events being encountered by kids

being treated with these things but they\'re not in

clinical trials because they keep getting ruled out

due to the exclusion criteria, does the adverse

events\--the MedWatch, does that capture those? If

the parents are screaming, do those\--like those

people that were the public presenters on Monday,

are their cases ending up in MedWatch?

DR. IYASU: Well, consumers also, you

104

know, send their reports through the MedWatch

program. Health professionals do. But as I said

before, 80 percent\--or more than 80 percent or 90

percent of the reports are actually from

manufacturers. Some of them may actually have been

reported directly to manufacturers from health

professionals, and then they are transferred to us.

The extent of the reports of adverse

events or experiences of adverse events by patients

directly is variable. It\'s small, actually.

Probably it\'s very underreported.

DR. O\'FALLON: Yes.

DR. IYASU: So we really don\'t have a way

of capturing that through a passive system such as

AERS, unless you go and do an active surveillance

system, which is a resource issue.

DR. O\'FALLON: Yes.

DR. CHESNEY: I think unless there are any

other pressing questions\--we\'re about a half-hour

behind, so maybe we need to move ahead. Dr. Iyasu

is going to introduce our next speaker.

DR. IYASU: Thank you. Our first speaker

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for this section of adverse events is Dr. Hari

Sachs. Hari is a professor of pediatrics with over

15 years of experience in private practice. She

also served on the FDA Non-Prescription Drug

Advisory Committee and is one of the FDA liaisons

to the American Academy of Pediatrics Committee on

Drugs. She will be presenting the adverse events

for ofloxacin and alendronate.

Dr. Sachs?

x DR. SACHS: Thanks again for that kind

introduction. Forgive me, I\'m a little

mechanically challenged, so if I screw up this

presentation, at least the mechanics of it, bear

with me.

I\'ll be discussing the adverse events for

ofloxacin, trade name Ocuflox, which is an

ophthalmic anti-infective that was approved in July

1993 for the treatment of conjunctivitis and

corneal ulcers due to susceptible bacteria in both

children and adults over one year of age.

Depending on the condition, one to two drops of

ofloxacin applied to the eye at frequent intervals.

106

The exclusivity was granted in March 2003 based on

studies of neonatal conjunctivitis, although

ofloxacin is not approved for that purpose.

As you can see from these statistics,

millions of prescriptions for ofloxacin were

written for both adults and children during the

one-year exclusivity period. Pediatric patients

accounted for almost one-third of these

prescriptions. And, in fact, pediatricians

prescribe almost as much ofloxacin as

ophthalmologists, and not surprisingly, the most

common indication is conjunctivitis.

Now I\'ll look briefly at the studies

performed for exclusivity, and as you can see, they

are posted on the Web.

The pivotal study was a one-week, active

control trial which compared ofloxacin and

trimethoprim sulfate treatment of conjunctivitis in

infants less than one month of age. The clinical

cure was based both on resolution of discharge and

erythema by (?) lamp exam and microbiology cure.

The safety of ofloxacin is comparable to that which

107

is seen in older patients in previous trials. But

although the clinical cure rate for ofloxacin

exceeded the active control, neither of the two

drugs exceeded the historical control, and,

therefore, the study was\--it was deemed that this

was not an approvable indication.

Note that the vehicle that\'s used that\'s

the historical control does contain benzyl

chromium, which has antibacterial properties.

The submitted data from this trial doesn\'t

really allow us to figure out why the cure rate was

low, why this study didn\'t seem to work. But

potentially there are factors related to the design

or conduct of the trial, the bacteriology of

neonatal conjunctivitis, or perhaps the time course

of it, or maybe a combination of all these factors.

In discussing the relevant safety

labeling, I\'m going to highlight information that\'s

either pertinent to pediatrics or the adverse

events. Ofloxacin is a Pregnancy Category C drug

since there are no studies in pregnant women and

there are some effects on animals. It is

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potentially excreted in breast milk. Under the

Pediatric Use section in precautions, there\'s a

statement that although the oral form of ofloxacin

has been associated with arthropathy in juvenile

animals, there is not an association for the

topical form.

There is a warning about allergic

reactions, including anaphylaxis, which details a

case report of Stevens-Johnson syndrome from the

topical preparation. Most adverse reactions to

ofloxacin, however, are really mild and include

ocular burning or discomfort and, very rarely,

visual changes such as photophobia or blurriness or

systemic symptoms may occur.

Now that you\'re familiar with the label,

let\'s look at the adverse events. As you can see,

there really are very few reported adverse events

for ofloxacin in all ages. And during the one-year

post-exclusivity period, there were only three

reports\--or three events, actually, all unlabeled,

two of which occurred in one adult and one that

occurred in a pediatric patient.

109

The pediatric event was a foreign report

that is also found in the literature of corneal

deposits in a 6-year-old who was receiving the

ointment. That\'s not available in the U.S. And,

in general, these types of corneal deposits

actually resolved by themselves and are thought to

be benign. This patient was actually treated with

scraping fairly early in the course. The natural

history actually is that it should have resolved.

With such few events, we really can\'t draw

a meaningful conclusion, and while this completes

the one-year post-exclusivity adverse event

monitoring, as mandated, we will continue our

routine monitoring of adverse events for this drug.

Are there any questions?

DR. NELSON: Just to repeat what I think

I\--you\'re unable to tell the ages of the pediatric

use. You can\'t tell how old the conjunctivitis

prescriptions were? In other words, is it being

used on-label above one year of age, or is there

any off-label use\--

DR. SACHS: Most of the use was on-label.

110

There\'s one database that captured some of the use

in kids under two, but it didn\'t separate out which

were under one. So it didn\'t help. It is

approximately 20 percent of the pediatric use for

that, the lower age group.

DR. CHESNEY: Thank you very much.

x DR. SACHS: Switching gears from one

system to another, I will now discuss the adverse

events that occurred during the post exclusivity

period for alendronate.

Alendronate, or trade name Fosamax, is a

biphosphonate which inhibits bone resorption by

osteoclast, and it was originally approved in

September 1995 for the treatment of osteoporosis in

adult women. Pediatric exclusivity was granted in

April 2003 based on studies of children with

osteogenesis imperfecta.

Currently, alendronate is approved only in

adults, and it\'s for the treatment of osteoporosis

for both men and women, its prevention in women,

and for Paget\'s disease. The dosage varies from

indication, and there are really no pediatric

111

indications.

As you can see from these numbers,

although Fosamax is widely prescribed in the U.S.

for adults, and the use is increasing, the use in

pediatrics is really minimal. There\'s like 10,000

prescriptions in pediatrics compared to 22 million

for adults. Alendronate is primarily used in the

outpatient setting with the lion\'s share of

prescriptions from internists, OB-GYNs, and family

practitioners. Pediatricians write very few of

these.

Osteoporosis and osteopenia were the

primary indications for therapy in adults, but in

pediatrics alendronate is used off-label for

treatment of osteoporosis and osteopenia either due

to underlying disease, such as renal or connective

tissue disease, or for its therapy, glucocorticoid

therapy, for example,, fibrous dysplasia, and as

you will see, osteogenesis imperfecta.

I\'ll briefly discuss the results of the

studies that were performed for exclusivity.

Both pharmacokinetic and safety and

112

efficacy and safety studies were performed to

evaluate the treatment of severe osteogenesis

imperfects, or OI, in pediatric patients ages 4 to

18\. The PK studies found that the oral

bioavailability of alendronate relative to the IV

dose was really similar in both children and

adults. Exclusivity was granted based on

submission of the 12-month analysis of this trial

in pediatric patients with OI, and both doses that

were used in the trial did significantly increase

lumbar spine bone marrow density, which was the

primary endpoint. But, unfortunately, a key

secondary endpoint was not reached, and that was

actually the occurrence of fractures either by

report or by x-ray.

The adverse events in the one-year

analysis appear comparable to those seen in adults,

and it\'s hopeful that this trial\--there\'s going to

be more data coming in on a one-year extension of

this trial.

Once again, I\'d like to highlight the

relevant safety labeling for pediatric patients.

113

Alendronate is considered a Pregnancy Category C

drug, with animal studies that have shown maternal

hypocalcemia that sometimes leads to early

delivery, and although there\'s no human data,

theoretically there can be an effect on the fetal

skeleton.

Due to significant gastrointestinal

irritation, alendronate is contraindicated in

patients who have a risk of esophageal emptying\--excuse me,

have a delay in esophageal emptying or

risk of aspiration or cannot stand upright. And

patients with hypocalcemia or allergy are told not

to take the drug. Esophageal perforation,

including ulcerations or erosions, are also

described in the warning section of the label.

Precautions include the recommendation to

monitor calcium and vitamin D status. And

gastrointestinal symptoms, such as abdominal pain

or nausea, musculoskeletal pain, headache,

dizziness, and taste perversion are the more common

side effects that are seen.

Now, since alendronate approval,

114

paralleling the relatively small percent of

pediatric use, pediatric adverse events really

represent only a very small percent of adverse

events. There were 17 total reports for pediatrics

out of 18,000 total reports. And this is kind of

indicated in the post exclusivity period as well,

with only four pediatric case reports that were

unduplicated. And there were no deaths.

The four reports include two cases of

hepatocellular injury, one patient that suffered a

drug-drug interaction potentially, and one infant

that had hypocalcemia and prematurity.

Hepatotoxicity was noted in two children

that were treated for steroid-induced osteoporosis,

and the details of their cases are reported on this

slide. But, briefly, liver dysfunction was

temporarily associated with the onset of

alendronate therapy and resolved after its

discontinuation and treatment with pulse steroids

in both patients. One patient did have underlying

liver dysfunction, and the other patient was on

methotrexate.

115

The drug interaction occurred in a 7-year-old with

JRA who was taking cyclosporine, and after

starting alendronate, the cyclosporine levels

decreased, and his disease flared. Once the

alendronate was stopped, the cyclosporine levels

returned to normal. There was some fluctuation in

baseline levels, so the exact interaction is

unclear\--I mean baseline levels of the

cyclosporine, that is, before the alendronate was

started.

The last case was the prenatal exposure

which describes hypocalcemia, hypocortisolism, and

prematurity in a male infant that was born to a

woman with multiple medical problems, including

gestational diabetes, and who was on multiple

medicines. Hypocalcemia is known to occur in

premature infants, infants of diabetic mothers, and

several of these therapies, as well as potentially

with alendronate.

So, in conclusion, only a handful of

adverse events were noted. Most did have

confounders or insufficient information to ascribe

116

causality. We did look at a preliminary analysis

of the adult hepatic events, and that does not seem

to raise any concerns. And this will complete the

mandated reporting for alendronate from BPCA, but

we will continue its routine monitoring.

Are there any questions?

DR. CHESNEY: Dr. Maldonado, and then Dr.

Nelson.

DR. MALDONADO: I observed that in the

ofloxacin you had only one adverse event, and it

was a different drug product, it was not the same

drug product in the United States?

DR. SACHS: Right. Well, it\'s the

ointment form as opposed to we just have drops.

DR. MALDONADO: So it\'s a different drug

product.

DR. SACHS: Correct.

DR. MALDONADO: And in Fosamax, also the

four reports were ex-U.S.

DR. SACHS: That\'s correct. They were

foreign reports.

DR. MALDONADO: Do you know if it\'s the

117

same drug product, or is there a possibility that

it is a different drug product?

DR. SACHS: I believe that it\'s the same

drug product.

DR. MALDONADO: And the reason I ask, for

those who are not familiar, you see internationally

the same names, and sometimes they are different

products actually, because the FDA approves drug

products, not drugs or\--and sometimes there are

different components in the drug product. So when

you include them, actually that\'s good that you

highlighted that, because that may be relevant to

the adverse events.

DR. CHESNEY: Dr. Nelson?

DR. NELSON: Just a question about

labeling, but not in the safety and efficacy

component. I don\'t understand, if, in fact,

there\'s been a pharmacokinetic study, why we would

say that the pharmacokinetics have not been

investigated in patients less than 18 years of age.

I mean, that\'s what the label says. Wouldn\'t we

normally include some pharmacokinetic data even if

118

we don\'t think safety and efficacy has been

established?

DR. MURPHY: No.

DR. NELSON: Why?

DR. MURPHY: Because you\'re giving it an

implied approval. You\'re giving the dosing. Now,

if the\--not always.

DR. NELSON: Well, we can\--

DR. MURPHY: Let me\--you know, that\'s a

whole big discussion, and you heard we have this

tension between trying to inform and not providing

a marketing freebie at the same time. So if that

pharmacokinetic study was done and found that there

was, you know, something very different going on or

some concern, then we could say on a dosing\--I\'m

talking about past. I\'m talking about prior

practice, okay? So whether that\'s all going to

change\--you know, it\'s good to provide you feedback

on this. I just wanted to say that in the past one

of the concerns that has been expressed has been

any information you put in the label about

pediatrics\--I\'m just starting from the big global

119

concern\--depending on what it is, if it\'s not a

safety, you know, warning, in essence provides a de

facto approval and/or an ability of the company to

market it.

As an example, they could go out and say,

well, look, FDA put this information in the label

about how to use it in kids. So there is that

balance of trying to make sure that it\'s clear if

we put information in, in what context that

information is put in the label.

Now, I mean, please proceed to say you

think we should have put it in the label; we\'re

interested in hearing that sort of stuff. But I\'m

just trying to provide why we routinely wouldn\'t

put information that we obtain into the label.

DR. NELSON: Just a quick response. I was

heartened to hear from Bob Temple yesterday that

that position was being readdressed. I previously,

until your comment, wouldn\'t have applied it to

just basically the pharmacokinetic information.

But I\'ll also point out that most people, myself

included, get my information from personal device-based

120

systems, which do include dosing data. And,

in fact, one of those two systems I have on my Palm

actually included depression as an indication for

an unlabeled use.

So I appreciate the concern about

encouraging it, but I actually think adding more

information might, in fact, discourage it if there

was an emphasis of making sure that information

was, in fact, accurate and then transmitted

accurately to clinicians. I know that\'s a whole

broader discussion, but\--

DR. MURPHY: I think we need to hear that.

I mean, that\'s what this committee is here for.

You\'re looking at the pediatric perspective on

this, and there has always been this tension. And

I think I\'ve told this committee before, there are

those of us who think we are mandated in some ways

to put some of this information in the label.

There have been others in the agency who have been

very concerned about doing that.

I think what you heard yesterday was a

very different approach that\'s being considered.

121

So we do want to hear these comments.

DR. CHESNEY: Dr. Maldonado, then Dr.

Fant.

DR. MALDONADO: I\'m just going to give you

a perspective, and Dr. Murphy is right, people may

misuse the information. I\'m not saying that that

wouldn\'t happen. But, for example, the drugs that

are being used off-label\--and we know\--and I\'ll

just give you the perspective of one that I\'m

working\--it\'s a company, and we rarely have the PK

data. And we now found out, although we believe

that the dose being used off-label was the correct

dose, and that\'s the dose that we use in the PK, we

found out that that\'s incorrect, that children are

being underdosed. This is an antimicrobial.

The clinical studies are ongoing, and they

may be ready in five years, by the way, because of

the long-term follow-up that we need to do. In the

meantime, people are using off-label this drug

incorrectly. And you\'re in the bind that you

cannot communicate that because it may be perceived

as, you know, promotion. But you want to

122

communicate it. It\'s difficult. I know exactly

the concern that the FDA has because it can be

misused. But at the same time, not conveying it,

it allows people to continue using the drug

incorrectly.

DR. NELSON: Can\'t your solution be\--I

assume there\'s some academic investigators

potentially involved at study sites, letting them

release at least the PK data in a publication? Or

does that also violate\--I mean, here it sounds like

you might even have a moral obligation to put out

that data.

DR. NELSON: Yes, the data has actually

been published in a poster format so people who are

more sophisticated in the area of infectious

diseases already know that that\'s incorrect. And

that\'s as far as we\'ve gone.

DR. MURPHY: But I think that this is a

perfect example of the quandary, because as all of

you know\--and you heard yesterday\--we have a

history of putting things in the label that nobody

ever finds anything about the information. I mean,

123

that\'s just the way life is. And with our health

care system the way it is right now, it\'s actually

getting worse, one could say, I think, as far as

physicians having time to access some of this

information in a timely manner.

But I would say, you know, if I were in

the Anti-Infectives Division and the company came

to me and said, oh, we\'ve got this information, we

want you to put it in the label, but we\'re not

ready to submit our application yet to show you

whether it\'s safe or efficacious, you can see what

the problem is.

DR. CHESNEY: Dr. Fant?

DR. FANT: One small point for completeness

related to the case of neonatal hypocalcemia.

You highlighted with an asterisk the drugs known to

be associated with hypocalcemia, but it may be

worth also putting an asterisk and highlighting the

condition of diabetes itself in addition to the

prematurity.

DR. SACHS: Yes, I mentioned that.

DR. FANT: Oh, okay.

124

DR. SACHS: I just put the medications,

but yes, oh, yes.

Behind these presentations, actually, are

a group of folks at ODS and in the divisions that

contributed to the report, and I just want to kind

of publicly acknowledge them as well: Jennie

Change, Renan Bonnel, Mark Avigan, Wiley Chambers,

Gianna Rigoni, Judy Shaffer, and Michael Evans. So

there\'s actually a lot of people that go into these

presentations that you don\'t see.

I would now like to introduce Dr. Susan

McCune, who is a neonatologist, whose previous

experience has included academic neonatal practice

at Johns Hopkins and Children\'s National Medical

Center. She recently received her master\'s degree

in education and has worked on computer-based

educational models for pediatrics. She will be

presenting the adverse events for fludarabine.

On a personal note, it\'s a pleasure for me

to be working with her again because she was, I

think, my chief resident when I was a resident at

Children\'s. Things go full circle.

125

x DR. McCUNE: Thank you, Hari.

It was an honor to work with Hari as a

resident, and it\'s an honor and a privilege 20

years later to work with her again at the FDA.

As Dr. Sachs said, I\'m going to discuss

the one-year post-exclusivity report for the

adverse events for fludarabine.

In terms of background information,

fludarabine, or trade name Fludara, is a synthetic

adenine nucleoside analog that primarily acts

through inhibition of DNA synthesis. It is

produced by Berlex Laboratories. Its indication in

adults is for the treatment of adult patients with

unresponsive B-cell chronic lymphocytic leukemia.

Of note, there are no pediatric indications that

are approved for this drug. The original marketing

approval date was April 18, 1991, and pediatric

exclusivity was granted on April 3, 2003.

I want to stop for a moment and talk to

you a little bit about the background of oncology

and pediatric drugs at the FDA, and I think this

gets a little bit to some of the questions that

126

you\'ve been asking about because oncology drugs are

a little bit different from some of the other

drugs.

There has been a special initiative at the

FDA to increase pediatric drug labeling for

oncology drugs and to prioritize the availability

of new oncologic agents to pediatric patients. To

achieve this goal, three items that I\'d like to

point out for your attention:

The first is the draft guidance for

industry that\'s entitled \"Pediatric Oncology

Studies in Response to a Written Request\" that was

published in June of 2000. The guidance is part of

this initiative to generate new knowledge to assist

practitioners and to provide early access to

emerging new drugs.

In addition, the Best Pharmaceuticals for

Children Act that was signed into law on January 4,

2002, established the Pediatric Subcommittee of the

Oncologic Drugs Advisory Committee and prioritized

new and emerging therapeutic alternatives that

could be available to treat pediatric patients with

127

cancer.

Another report entitled \"Patient Access to

New Therapeutic Agents for Pediatric Cancer,\" which

was published in December 2003 and was a report to

Congress, was a report that identified areas in

pediatric drug development that could be improved

to facilitate access to new agents.

Now I\'m going to focus a little bit on the

trials that were done for exclusivity for

fludarabine.

Exclusivity was based on data that was

submitted from two previously published COG trials:

CCG-097 and CCG-0895. CCG-097 was a Phase I dose-finding

and PK study of a loading bolus followed by

a continuous infusion of fludarabine in patients

with acute non-lymphocytic leukemia, acute

lymphocytic leukemia, and solid tumors. CCG-0895

was a Phase I/II dose-finding, PK, and

pharmacodynamic study of a loading bolus followed

by continuous infusion of fludarabine, then

followed by a loading bolus and continuous infusion

of Ara-C in children with previously treated acute

128

leukemias.

I\'m going to talk a little bit in detail

about the first trial, which was CCG-097. There

were two groups of patients, first those with solid

tumors and those with the acute leukemias. The

patients with the solid tumors reached a maximum

tolerated dose because of dose-limiting toxicities

that were hematologic\--in other words,

myelosuppression. The patients with the acute

leukemia, the goal was marrow ablation, so their

maximum tolerate dose was not reached based on this

toxicity\--toxicity associated with the solid

tumors, but their dose was limited by the concern

for potential CNS toxicity that had been seen with

adults. Of note in this trial, there was one

complete and three partial remissions in 26

evaluable children with ALL.

The pediatric adverse events that were

noted in this trial and are included in the label

are marrow suppression, especially of platelets,

fever, chills, asthenia, rash, nausea, vomiting,

diarrhea, and infection. No peripheral neuropathy

129

or pulmonary hypersensitivity was seen in these

trials.

The second trial, CCG-0895, which I had

previously told you was a sequential administration

of fludarabine followed by Ara-C, was undertaken in

31 patients either with ALL or AML. Of note, in

the patients with ALL there was a 33-percent

complete or partial response, and in those patients

with AML, there was a 50-percent complete or

partial response. This study was not able to

provide data on the efficacy of fludarabine alone,

but did provide efficacy and safety data for the

combination.

I\'d like to just point out\--let me see if

I can do it here\--that this information from the

first trial, CCG-097, has been included in the

label as of October 2003. There are two parts of

the label that have been changed. The first is the

clinical pharmacology in special populations

pediatric patients, which highlights that steady-state

conditions were reached early. And then in

the precautions section, pediatric use, this is a

130

description of that trial that I just told you

about, followed by the treatment toxicity that I

also pointed out to you.

In terms of drug use trends in the

outpatient setting or sales of fludarabine, this is

considerably different from what Dr. Sachs

presented to you with her millions of

prescriptions. Approximately 280,000 vials only of

fludarabine were sold in the U.S. annually from May

2001 through April 2004, with no significant

increase seen after exclusivity. And as Dr. Iyasu

pointed out to you, this particular database is one

that does not divide it up in terms of pediatric

and adult use. Just as you would expect,

fludarabine was primarily sold to clinics and non-federal

hospitals during the 12-month post-exclusivity period.

In terms of drug use trends in the

inpatient setting, where we do have some pediatric

data, Premier data showed us that pediatric use

accounted for 3 percent of discharges between 2002

and 2003 in which fludarabine was billed. And CHCA

131

data demonstrated that from October 2002 through

September 2003, there were 95 discharges associated

with fludarabine, which were essentially unchanged

from the previous year.

Now I\'m going to switch gears and talk to

you about the adverse event reports for fludarabine

in the one-year post-exclusivity period from April

2003 to May 2004.

The total number of reports for all ages

were 300, with approximately a third of them

occurring in the United States. As expected,

almost all of them were serious, and over a third

of them involved deaths.

In terms of the pediatric reports, all of

them were serious. There were ten unduplicated

pediatric reports, only one of which was in the

United States, and the outcomes for three were

death, and seven were hospitalized, one which

suffered continuing sequelae.

Of those ten pediatric patients, the

recorded use was for six preconditioning for bone

marrow or stem cell transplant; for three, AML

132

relapse; and for one, JMML with splenectomy prior

to bone marrow transplant. The age for these

reports was predominantly in the 2 to 5 age range

with six reports, one each in the one month to less

than 2 years, and the 6 to 11 year age ranges, and

two in the adolescent population.

Dr. Maldonado, this may get to your

question earlier. These are all the adverse event

reports for fludarabine in the one-year post-exclusivity

period, both adults and pediatric

patients. As you can see, there are a significant

number of adverse events. Those that are

underlined are actually unlabeled events, including

increased bilirubin, abdominal pain, and then three

related to either drug ineffective or disease

recurrence. In the pediatric population, the only

unlabeled event was abdominal pain.

I\'m now going to give you a brief

discussion of each of the ten pediatric patients

followed by a summary of their categories and a

comparison with the adult information in the label.

There were three deaths. The first was a

133

four-year-old with ALL who received fludarabine for

preconditioning for stem cell transplant. The day

after transplant, she developed fever, shock, and

multi-organ failure. This was one of the cases

that also reported abdominal pain.

An eight-year-old with ALL who received

irradiation, fludarabine, and cyclosporine followed

by stem cell transplant, who six days after

transplant became febrile with a rash, generalized

edema, tachycardia, abdominal pain, and cardiac

arrest.

Of note, one of the later cases is a

cardiac tamponade patient. We don\'t have

additional information, but the tachycardia to over

200 along with the edema could be possibly

concerning for that as well. But there is no

additional information.

And the third and final death is a 13-year-old

with bone sarcoma of the rib who received

fludarabine as preconditioning for stem cell

transplant and then developed carcinomatous

pleurisy and died of disease progression.

134

In terms of the seven hospitalizations,

there was an 18-month-old with hepatic veno-occlusive

disease after bone marrow transplant for

beta-thalassemia. There was a two-year-old with

relapsed AML who developed photophobia on the FLAG

study, which is fludarabine, cytarabine, and

granulocyte colony stimulating factor. There was

no photophobia noted on rechallenge.

And then I want to highlight an additional

visual disturbance in a three-year-old with

relapsed AML also on the FLAG study that developed

bilateral blindness, which resolved leaving some

degree of blindness, and that\'s the sequelae that I

spoke of.

There was a four-year-old with AML relapse

who developed encephalopathy and recovered.

The only United States case is a four-year-old

with JMML with splenectomy in preparation

for bone marrow transplant, who developed fever and

pneumonia.

There was a five-year-old with AML after

bone marrow transplant who developed aphasia,

135

vigilance disturbance, and non-specific

encephalopathy. This is a foreign report. It\'s

not clear whether vigilance disturbance is a

disturbance of state associated with encephalopathy

or could potentially also be visual disturbance,

although most likely just a disturbance associated

with the encephalopathy.

And then, as I previously mentioned, a 13-year-old

with bone marrow transplant for aplastic

anemia who developed cardiac tamponade and cardiac

failure four days after transplant, who recovered

with diuretics and pressors.

So, in summary, there were ten clinically

significant pediatric adverse events, and if you

break them down into four categories, there was

cardiac failure in two, cardiac tamponade in one,

and cardiac arrest in two. This is labeled for

adults for edema and pericardial effusion. The

abdominal pain that I pointed out to you before

that was not labeled in adults, it is labeled for

nausea, vomiting, anorexia, diarrhea, stomatitis,

and GI bleeding in adults. And as I pointed out,

136

the two patients that had abdominal pain in the

pediatric age range were those with multi-organ

failure and death.

There were two pediatric patients with

blindness and optic nerve disorder, and this label,

as I will show you in a moment, is labeled for

visual disturbance and blindness in adults. And

encephalopathy is also labeled in adults.

Just to give you an idea in terms of

whether this is a different signal from what\'s seen

in adults, I showed you the most common adverse

events in terms of those that were more than 20.

In this same period of time, all of these events

were reported in adults in the range of three to

five adult reports.

And I just wanted to show you, this is the

boxed warning for Fludara, and this gets at a

couple of issues that were discussed actually

yesterday. This drug should be administered under

the supervision of a qualified physician

experienced in the use of antineoplastic therapy.

In addition, it is labeled in the boxed warning

137

that it is associated with severe neurologic

effects, including blindness, coma, and death.

Also labeled here are fatal autoimmune hemolytic

anemia, and down here a warning about the

combination of use with pentostatin and fatal

pulmonary toxicity.

So, in summary, there are labeled and

unlabeled adverse events for fludarabine that have

been reported. There are a number of pediatric

adverse events that were reported in the post-exclusivity

period that were not recognized in the

clinical trials that were done for exclusivity.

These adverse events, however, have been labeled

for adults. These serious adverse events include

encephalopathy, blindness and other visual

disturbances, and cardiac tamponade and failure.

These patients tend to be on very complicated, pre-

transplant regimens that involve multiple

medications and immunosuppression. I just want to

note that this completes the one-year post-exclusive adverse

event monitoring as mandated by

BPCA. But the FDA will continue its routine

138

monitoring of these adverse events for this drug.

Any questions?

DR. CHESNEY: Thank you very much.

Comments, questions? We need Dr. Santana,

who is in Oslo.

Any other comments? Dr. Murphy, are there

any\--

DR. MURPHY: I think, you know, this is

just one of the things we\'ll be looking at in the

future when we review these and we don\'t think we

see anything going on. How much information do you

want? Do you want us to present it? Do you want

us to send it to you beforehand? When we say we

are going to no longer do\--when we say this

completes the exclusivity reporting, it means that

this process will no longer occur, and that we are

basically telling you that we think that that

appears to be an appropriate outcome, unless you

tell us something differently than that. We\'ll now

go back to the usual process of just the Office of

Drug Safety doing their reviews and we won\'t be

reporting this to you.

139

So I did want to make that clear to the

new committee members. That\'s what that means when

we say that. We don\'t have any specific questions

for this product.

DR. CHESNEY: Dr. Fant?

DR. FANT: Yes, just a question. Out of

curiosity, how did the signals that emerged from

the use of this drug, given the complex nature of

the disease and the drug regimens that these kids

are on, compare with the signals that emerged in

previous reports for some of the other drugs?

DR. McCUNE: For the other oncologic

agents or other drugs in general?

DR. FANT: Well, the other oncologic

agents in these types of patients. Any way to sort

of get a sense of whether there\'s something unique

about these signals versus the others?

DR. McCUNE: I actually reviewed two

oncologic drugs the last time we presented for this

committee, and I think the process that we\'re

really looking for is what you all have pointed

out: Are there substantial differences from the

140

adult population? Are there substantial

differences from what\'s in the label that should be

potentially added to the label? Although that\'s

very difficult given all the confound\--the small

numbers of patients and the confounding. And I

think that it becomes very difficult because most

of these drugs are not used except in patients who

have recurrent disease, so they have disease

progression. They\'re also on multiple other drugs

and multiple other regimens.

So it can be difficult to pull out a

signal. That\'s why we very carefully look at each

one of these adverse event reports to try to see if

maybe there\'s something more there or if there\'s a

relationship that does not show up in the label for

the adults. And so far, with the three drugs that

we\'ve reviewed in the last year, I haven\'t seen a

substantial difference. They\'re very low numbers

of usage for the drugs in general in the

population, 200,000 versus millions of

prescriptions. And then the pediatric use in that

is very low. Because of that low number, that\'s

141

why there\'s been this initiative to try to get drug

labeling for oncologic drugs because, otherwise, we

wouldn\'t have the data to be able to do labeling or

to be able to get these drugs to the population

quickly.

DR. CHESNEY: Dr. Ebert, and then Dr.

Nelson.

DR. EBERT: When you identify adverse

events that have not been seen previously in

pediatrics but have been seen in adults and are in

the labeling, is the implication that the labeling

does not need to be modified or that it does need

to be modified?

DR. McCUNE: In general, when it\'s been

stated in the label for adults, that\'s considered

labeling. If there were something where there was

a substantial signal without the confounding

variables, that would be something that could be

discussed. But, in general, unless there\'s a very

strong signal that is different from what\'s seen in

the adults, the label is considered to be adequate.

DR. CHESNEY: Thank you. I had that same

142

question, so thank you.

Dr. Nelson?

DR. NELSON: Just a comment before leading

up to a question. I noticed the significant amount

of pharmacological information in the label, as you

pointed out, in terms of pharmacokinetics, and I

speculate I know part of my comfort level with the

use of these drugs is the fact that in the United

States 90 percent of the children are treated on

protocol, and the chances of this being used off-label are

exceedingly low. Is that different in

Europe? Is this either labeled or do they have\--I

mean, I\'m just wondering why this seems to be used

more frequently. Maybe, you know, in that case, I

assume it\'s not labeled for a pediatric indication

in Europe, but they must not have as much of a

control over what happens to where someone\'s

obviously using it for bone marrow transplant

protocols.

DR. McCUNE: I don\'t know the answer about

labeling in Europe.

DR. MURPHY: That\'s one place we haven\'t

143

looked. But I do think that you\'re making a good

point. There has been a concerted effort within

the FDA, working with both NCI and the American

Academy of Pediatrics, to address the issue that

was being brought up here. But the fact is that

you won\'t have these products in Phase III trials

for children. I mean, that just is not the process

that happens for oncology drugs, though they\'re

almost all\--most of the children are in trials. It

has to do with the paucity of, you know, the

population and the ability to actually conduct

Phase III trials.

I know this seems schizophrenic, so I

just\--so dealing with that issue, the quandary was

we would never have products labeled for kids who

have cancer which\--yet we would have a tremendous

amount of information. So there was an entire

process and a number of meetings to look at how can

we make the information available that is developed

for this population. That\'s why there\'s a guidance

on how to do that and how you can\--and encourage

the development of these products and research into

144

these products for children. And that\'s why the

statement was that you don\'t actually have to have

the product approved for children for certain

indications to get this information into the label.

But it is, you know, a product, a disease-specific

process, and it\'s appropriate that information will

go into the label for the oncology drugs.

DR. NELSON: But I guess if the comfort

level in doing that is because there won\'t be the

opportunity given the professional organization for

extensive off-label use, then I guess as a group at

some point in the future we should tackle about how

one could discourage off-label use while at the

same time providing information.

DR. McCUNE: That\'s one of the reasons why

I wanted to point out in the boxed warning that it

does state that a qualified physician using anti-neoplastic

therapy be the one to administer the

drug.

DR. CHESNEY: Dr. O\'Fallon?

DR. O\'FALLON: Well, you know, this is a

real quandary because you\'re absolutely right that

145

the vast majority of children are on these studies,

which is wonderful because they are being monitored

very carefully. The ones that don\'t make it on to

the protocols are usually, in my opinion, ones with

comorbidities or some\--or there\'s such an advanced

disease. So they\'re starting to treat them with

these things.

I\'m wondering if given the fact that a

year doesn\'t\--given the fact that there isn\'t a

huge population of off-label use out there, a

year\'s data doesn\'t give us very much of a chance

to see off-label problems. Do you see what I mean?

If they\'re treating\--a million kids were treated

with something in that year, then you\'ve got a

pretty good idea\--a pretty good chance to pick up

anything that was somehow missed in the clinical

trial. But if it\'s a very small number of kids

that were treated in that year, then we really

don\'t have very much of a chance of picking up

anything either.

DR. McCUNE: The division continues to

follow reports associated with the use of this

146

drug, so it\'s not like we don\'t have any follow-up.

But we just wouldn\'t come back to present it

necessarily to you unless there was something that

would be\--

DR. O\'FALLON: You don\'t diminish your

surveillance. You just diminish your reporting to

us. Is that what we\'re talking about?

DR. McCUNE: That\'s correct.

DR. MURPHY: Well, we diminish going back

and reporting to you. We don\'t go back and look at

the, you know, trials that you\'ve already seen. I

mean, since that process has occurred. If

additional studies had come in, you know, there

might be an opportunity. But I think the only

thing I would say is that if there\'s something that

concerns you in the report and it was combined with

the issue of either a small population or, as some

of you know from the prior committee, the

exclusivity is granted before the approval

sometimes. That\'s changing because of the timing

on the approvals, but there may not actually be

much postmarketing in some certain situations. If

147

those situations\--if you are concerned about

something and either of those two situations

exists, you could recommend that we come back and

report to you relevant to whatever, you wanted more

time to see what was happening. I mean, that is an

option I think this committee has actually utilized

earlier on when we had a very short postmarketing

period.

But, again, I think just having a short

postmarketing period wouldn\'t be the only reason to

do it. It would be because there was a question or

some concern that you would like us to come back

and report to you about.

DR. O\'FALLON: Isn\'t the purpose of

postmarketing to pick up something that probably\--that could

have slipped through the cracks on the

studies? That\'s all. If we don\'t give ourselves a

very good chance at doing that, we\'re not going to

have a chance to pick it up as much. That\'s all.

DR. MURPHY: Yes, I mean, and for the

things you mentioned, I mean, the studies often\--of

course, the cancer studies\--but, still,

148

particularly in other studies, they\'re much more

exclusionary, and when it gets out there, it\'s used

in the broader population. And as has been pointed

out before, AERS is good over time picking up the

rare, serious events that occur. So if those are

concerns that you have, then you could recommend

that we continue to report to you.

DR. CHESNEY: Thank you very much. Could

I suggest that maybe we take a ten-minute break

before the next speaker? I did want to ask if

there was anybody here for the open public hearing.

Nobody has registered yet, but we just wanted to

check.

\[No response.\]

DR. CHESNEY: No. So I think if we could

come back in ten minutes at 10 after 11:00, and

we\'ll continue on with all the subsequent

presentations. Thank you.

\[Recess.\]

DR. CHESNEY: I think we\'re ready to get

started. It looked like we should be able to

finish pretty close to our allotted time for those

149

with appointments with planes, trains and

automobiles at the end of the meeting. So we\'ll

move on to the next presentation.

DR. McCUNE: Thank you. It gives me great

pleasure to introduce Dr. Jane Filie. Dr. Filie is

a general pediatrician and pediatric

rheumatologist. After years of doing basic

research on connective tissue disorders and

genetics at the NIH, Dr. Filie was a pediatrician

in private practice prior to joining the FDA.

Today Dr. Filie is going to talk to you

about desloratadine.

x DR. FILIE: Thank you, Dr. McCune.

Good morning, everyone. I would like to

present the adverse event review for desloratadine

during the one year post exclusivity.

Desloratadine is an antihistamine by

Schering Corporation. It was originally approved

in December 2001, and pediatric exclusivity was

granted in February 2003. It is indicated for the

treatment of seasonal allergic rhinitis in patients

2 years and older, and for the treatment or

150

perennial allergic rhinitis and chronic idiopathic

urticaria in patients six months and older. The

recommended doses are listed on the slide.

I would point some facts regarding

loratadine, which is the predecessor of

desloratadine. Loratadine is approved for children

2 years and older, whereas desloratadine is

approved for children 6 months and older.

Desloratadine is the major metabolite of loratadine

and possesses similar pharmacodynamic activity. It

also has less extensive first-pass metabolism and a

longer half life than loratadine.

Now, the drug use trends for

desloratadine. It accounted for 15 percent of the

prescription non-sedating antihistamine market from

March 2003 to February 2004. The total number of

prescriptions increased slightly from 9.8 million

to 10.2 million during the same period. Pediatric

prescriptions accounted for 1.3 million

prescriptions.

For pediatric exclusivity 246 children, 6

months to 11 years of age were exposed to

151

desloratadine in three two-week, double-blind,

placebo-controlled safety studies. The efficacy of

the drug was extrapolated from the adult efficacy

data. The safety studies identified a subset of

pediatric patients who are slow metabolizers of

desloratadine, approximately 6 percent of all

pediatric and adult patients, and 17 percent of the

African-American patients. There was no difference

in the prevalence of poor metabolizers across age

groups, and there was no significant difference in

adverse events, laboratory tests or vital signs

between the pediatric poor metabolizers and normal

metabolizers who received desloratadine or placebo.

The adverse events that occurred more than

2 percent during the clinical trials, which

included adults and children over 12 years of age

are listed on this slide.

In the pediatric clinical trials there

were no adverse events reported that occurred more

than 2 percent of patients in the age group of 6 to

11 years of age. The adverse events that occurred

more than 2 percent in frequency greater than

152

placebo are listed on the slide according to

different age groups as well.

During the one-year post exclusivity,

there were 185 reports for all ages. Among the 185

reports there were 20 pediatric reports, 6 of them

in the United States. Among the 20 pediatric

reports, there were five serious pediatric event

reports and there were no deaths.

The pediatric adverse events reported are

listed on this slide. Even though there were 20

reports, these events do not add to 20 because some

reports contained more than one event. The

underlying events are unlabeled events.

I now proceed with a synopsis of the

serious adverse event reports. 12 year old on

desloratadine and nasal beclomethasone for

unspecified allergy had bronchospasm and shortness

of breath, hospitalized for an unknown period of

time.

An 11-year-old on 5 milligram

desloratadine, unknown indication, developed two

asthma attacks within one month requiring

153

hospitalization. The patient had five doses of the

drug between the asthma attacks without difficulty.

And a 6-year-old on desloratadine, 2-1/2

milligrams daily for urticaria, presented with

Kawasaki disease three months after the initiation

of treatment.

A 5-year-old on 1.25 milligrams

desloratadine daily for cough and nasal secretion

experienced somnolence, bradycardia, diplopia,

dizziness and motor uncoordination, and this

patient was hospitalized for 12 hours.

Last: a 2-year-old with a history of

bronchiolitis and wheezing on desloratadine, 1.25

milligrams, for coughing and rhinitis, who

experienced status asthmatic as requiring

hospitalization on two successive days.

Notice that these were all non-U.S. cases.

Although not reported as serious adverse

events, there are a few adverse event reports that

were clinically significant. For example, a 5-year-old on

desloratadine, 125 milligrams daily for

rhinitis, experienced two days later somnolence,

154

disorientation, and an unspecified extrapyramidal

disorder, one week later became unconscious, and

recovered one day after the drug was discontinued.

Another relevant case was a 4-year-old

girl on 2-1/2 milligrams of desloratadine daily,

had been on the drug for a week from mosquito bites

and no other medications, experienced spasms of the

upper body which resolved weeks later after

discontinuation of the drug.

Lastly, a 3-year-old on desloratadine for

8 days of a known dose and specified medication, no

concomitant medications, experienced torticollis,

and no other data was available.

Also notice that these are all cases that

occurred abroad.

In summary, there were a few pediatric

adverse event reports during the pediatric

exclusivity period. There are no new safety

concerns regarding the use of desloratadine in the

pediatric population. This completes the one-year

post exclusivity adverse event monitoring, as

mandated by BPCA, and the FDA will continue its

155

routine monitoring of adverse events for this drug.

DR. CHESNEY: Any questions? Yes, Dr.

Newman.

DR. NEWMAN: I have two questions. You

listed a whole of kind of common pediatric things

that were listed as more commonly occurring with

medication than placebo. Were any of those

statistically significant?

DR. FILIE: Which\--

DR. NEWMAN: This was in the exclusivity

trial, the fever, diarrhea, upper respiratory tract

infections, coughing, all of those things. It\'s

your ninth slide. Greater than 2 percent in

frequency, greater than placebo.

DR. FILIE: No. These were really not so

much different, and the range, the incidence of

these side effects, adverse events, was around not

more than 4 percent each, and they were not really

clinically significant.

DR. NEWMAN: But all of these were more

frequent with drug than with placebo?

DR. FILIE: Exactly. Which slide are you

156

talking about?

DR. NEWMAN: It\'s Slide 9.

DR. FILIE: Yes. These did occur more

than 2 percent, and more frequently than placebo.

DR. NEWMAN: And were there some sort of

equal number of adverse effects that happened less

often with medication than placebo? I mean, I

don\'t know how\--if you look at 100 different

things, and your standard is just more rather than

statistically significant more, you\'ll find a

bunch.

DR. FILIE: You\'re asking if there were

some adverse events that occurred more frequently

in placebo than with the drug?

DR. NEWMAN: Right.

DR. FILIE: Probably so, but I do not have

the numbers. I cannot tell you that, but this is

what is expressed in the label. Usually what they

will have on the label is what occurs more

frequently on the drug.

DR. NEWMAN: Unless you can tell how often

it occurred with both and whether any of them are

157

significant, this kind of labeling just doesn\'t

really help at all. It\'s not informative.

DR. FILIE: Yeah. Would anyone like to

add? I would like to invite the Review Division if

they would like to chime in and give any additional

information. But as far as I can tell without

looking at the reviews, the clinical reviews right

now, I don\'t have the numbers.

DR. MURPHY: I think what you\'re getting

at is how we do adverse event reporting in our

labels. Is that the issue?

DR. NEWMAN: I\'m just saying, you know, if

you look for 100 different things and your only

standard for reporting it is that it occurred more

often with\--I mean they\'re not going to occur at

exactly the same rate with drug and placebo.

They\'re not going to occur at exactly the same

rate, so the fact that it occurs a little more with

drug than placebo doesn\'t really indicate anything,

you know. The question is does it occur either any

one outcome statistically significantly more, or a

lot more, or if you add them all together and say,

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okay, any adverse event, was any adverse event, if

you pool all these together, are one or more

adverse events more likely with drug than placebo?

As a clinician who sees a lot of kids who

get antihistamines and sees all of these things on

the list every day, I mean a lot, I suspect that

this is not a real association, but then why put it

on the label? It just doesn\'t help me at all.

DR. MURPHY: What is done is if there are

statistically significant differences in the

trials, clearly that is put into the label, okay?

But what is also then done\--and one could argue the

usefulness of that\--but because trials are very,

you know, as we\'ve discussed, limited in number,

limited in duration, limited in the population,

what is also provided is additional information

about adverse events that occurred more frequently

in the treatment group than in the placebo group.

I mean you\'re right from a mathematical point of

view, but it is felt that because we know we\'re

only looking at a limited amount of data that it is

appropriate to define that which we think is

159

clearly statistically significantly different and

that which we think is just reported that was seen

in the clinical trials.

And actually there\'s been discussion of

should we even be including those things that are 1

percent\--what percentage should we have a cutoff

and how useful it is? But that is some of the

thinking behind why doing it, is that you don\'t

really know what the entire context\--I mean the

entire spectrum might be, and this is the

controlled clinical trial against placebo, and you

know that in a population you\'re going to have

background noise, so at least you can report

against placebo what was seen.

Is Badrul here? Would you like to comment

on how your division reports, particularly I think

for the antihistamines. But it gets to the bigger

labeling issues.

DR. CHOWDHURY: I\'m Dr. Badrul Chowdhury,

the Division Director in Pulmonary and Allergy

Drugs.

What you\'re asking is a pretty broad

160

question I think, is not necessarily applicable to

this drug as a single entity that applies across

how an adverse event is reported in the product

label following clinical trials.

The general practice is\--I mean knowing

it\'s a very limited database for a clinical trial,

it\'s usually a few hundred to thousands, and you

cannot really capture everything that has happened

or could happen. The practice generally is to look

at the numbers that happened with the drug, look at

the numbers that happened with placebo, and make

some reasonable cutoff of event that is more

commonly happening with drug than with placebo, and

put the numbers then.

Statistical influential statistics on

adverse events is completely useless because you

cannot really put a p-value against an adverse

event and conclude it is significant or not. It

really isn\'t worth an observation. And it is

really during clinical practice that more and more

is known, and adverse events, as it is reported,

gets modified. It is not uncommon for a drug to

161

have an adverse event that you did not think of as

being a drug-associated adverse event, but later on

there\'s cases it bears out to be the case.

DR. NEWMAN: I would disagree with that,

that there\'s no way that in practice anyone would

pick up any of these adverse events as being drug

related in the absence of a randomized trial

because the background noise for all of these

things is a lot.

DR. CHOWDHURY: Nobody\'s saying that is

drug-related or drug-causes adverse events. It is

just that these were observed. And add that to the

interpretation of ultimate use because if you see

something which is happening more commonly with the

drug and not happening with placebo, I mean, it\'s

not possible to go after each and every adverse

event and try to make a cause and association if it

is caused by the drug or not. I mean, just cannot

happen in development in the limited time period.

We\'re just reporting what was seen.

DR. NEWMAN: Okay. My guess is this is

not the time to try to\--

162

DR. CHOWDHURY: Oh, it probably is not,

and this is really I think a more broader issue of

adverse event reporting in the product label that

comes out of clinical trials across drugs and

across drug classes done specifically for

desloratadine.

DR. NEWMAN: So maybe we could discuss it

more at another time, but just as a consumer of

this information, I find it pretty useless.

DR. CHOWDHURY: I mean I would really not

discount it to that of an extent because I mean

there are also adverse events that are here which

actually may even turn out to be meaningful. I

mean if I just pick an example for here, appetite

increase. Somebody can say it\'s completely

useless. But if you really go back and look at all

antihistamines, it is not uncommon for some older

antihistamines actually to cause persons to gain

weight. This was the case with older

antihistamines. Nobody would really link that

association, but it is known that some older

antihistamine which is not marketed in the U.S. any

163

more, actually caused increased weight.

And when you see in this report this

appetite increase, I mean you can discount it being

useless, but who knows? It actually may in the

future might turn out to be useful.

So it\'s just a pure reporting of the

number that were seen, not necessarily making a

conclusion if that is associated with the drug or

not.

DR. MURPHY: Again, it gets back to what

do you think you\'re trying to achieve? I think the

thought here is that, again, this is the controlled

trial against placebo. You\'re going to have

problems once it\'s out with all the confounders of

background noise, and that it\'s appropriate to let

people know in a controlled trial, this occurred

more frequently than placebo, not making

attribution. But over time you may, as Badrul

pointed out, we will come back and revisit that

which has been labeled from controlled trials and

see if it\'s becoming relevant or more relevant. I

guess better more relevant.

164

DR. CHESNEY: Thank you. I think this

could be something that was readdressed, and Dr.

Ebert and Dr. Nelson have questions. I also.

I\'ve wondered, what stands out to me here

is the movement disorders. What do you make of

that, and is that a common finding in other

antihistamines. I\'m not used to using it to

prevent them.

DR. FILIE: Usually it is not common to

occur with antihistamines, but these are newer

generations of antihistamines. It was not

described in the clinical trials either adults or

children. This was never described. So this is

why we brought it up as important, and again, we

need to report the information as it is and the

numbers as they are, but, yeah, it had not been

described in the clinical trials for adults of

children. The earlier generations, like super

heptadine, which was an older antihistamine, was

known to cause some purposeless movements in rats

in preclinical studies. So again, this is

something that I think we need to watch.

165

We\'re looking at an ocean and these little

signals pop here and there, and probably only with

time and more numbers, we\'ll be able to make a

better interpretation of this.

DR. CHESNEY: Thank you. Dr. Ebert and

then Dr. Nelson.

DR. EBERT: Could you provide a little

more detail about the two cases of congenital

abnormalities?

DR. FILIE: Certainly. Let me see if she

can pull this. It\'s a back-up slide. Can you find

it? It\'s called maternal exposures.

These were two cases, and again, these

reports have very little information. They are

very vague, and it\'s very difficult to make any

attribution of congenital malformation and link

this to the exposure to the drug. As you can see,

one baby was born with cryptorchidism and hernia

and was exposed to desloratadine for five days,

unknown gestational age, and the mother had

concomitant use of amitriptyline. And the other

case was a baby born with a cleft lip and palate,

166

and was exposed to multiple medications for an

unknown length of time and unknown period of the

pregnancy.

So it\'s really very vague and difficult to

make any assumption given even the background rate

of the occurrence of these malformations.

DR. CHESNEY: Dr. Nelson and then Dr.

Fant.

DR. NELSON: I think you correctly

observed that these are isolated events in an

ocean, but I\'d like to comment on the size of the

ocean. What strikes me is that these are non-USA

reports that you\'re reporting, and that if we want

to try to get some estimate of frequency that what

we really need\--and I guess I would be making Dr.

Iyasu\'s job more difficult\--the European Union, if

that\'s where they\'re from, is a smaller market than

United States, and in fact it may then reflect a

higher frequency than we might think if we look at

our 10 million prescriptions here. We don\'t know

then how many prescriptions were actually written

for the population that\'s reporting these events.

167

DR. FILIE: That is correct.

DR. NELSON: And it also raises an

interesting question whether their ascertainment

system\'s better or whether their physicians are

just more socialized into\--I don\'t use that term

politically\--into reporting, etc. But the data

that is not comparable, we have isolated events out

of a market that we don\'t have the denominator, and

we have a denominator out of a market we have no

isolated events. So either we\'re much safer here,

or what? So comment.

DR. FILIE: Exactly, and I think you\'re

correct.

DR. IYASU: Could I make a comment here?

I wouldn\'t presume to sort of evaluate how

different our systems are. I won\'t make a comment

about that.

But in terms of foreign reports, what we

get is probably a very small percentage of the

actual volume because the requirements are there

for serious events to be preferentially reported

from those serious sources. There\'s no requirement

168

to. So there is also, you know, many\--there\'s more

focus on the serious events. But in terms of

exposure, I don\'t know of any database that we have

access to at FDA that will sort of estimate what

the exposure that was in Europe, although they do

have their own databases as well. And IMS has

different streams that also is only probably making

estimates in drug exposures in Europe.

So I don\'t think we have the right

databases to try to tease out what the differences

are, but I think we need to be careful, wherever

the reports come from, that if there is an

opportunity to explore them further, that would be

an important activity which you say you would make

my job more difficult. But I think this is

something that we can entertain.

DR. CHESNEY: So you can add a European

database to your American database in your spare

time.

\[Laughter.\]

DR. CHESNEY: Dr. Fant?

DR. FANT: Just one comment that stems

169

from one of your case reports, and I think it just

underscores the importance of these narratives, at

least from what I can glean.

In the 5-year-old, who basically over the

course\--two days after starting the medication,

over the course of a week, developed somnolence,

disorientation, unspecified extrapyramidal

disorder, which seemed to progress over a week to a

state of unconsciousness, and then recovered one

day after the drug was discontinued. What you told

us was that one of the features of this drug was

its relatively long half life. So it\'s just kind

of perplexing, just from a pharmacokinetic

standpoint how such severe symptoms\--now they may

be connected; this may be a connection, but it\'s

kind of a strange one from the way I interpret

this, and it\'s worth noting because it may be real

or it may be something that emerges as some bizarre

quality related to this particular drug in terms of

the idiosyncratic reactions it may elicit in

people. But I just don\'t understand how such

severe symptoms can resolve in one day after being

170

on a drug with a long half life for a week.

DR. FILIE: Yes. I agree with you. And

again, these reports are very vague, so it doesn\'t

give us much information. And you\'re right, how

could he just recover in one day how disoriented

and somnolent this child was. Could be that this

child would have been in that category if this all

metabolized and really had a more significant

presentation of the side effects. We just don\'t

know and can\'t tell just from the report.

DR. CHESNEY: Thank you very much.

I think we\'ll move on to the next topic of

adverse events for budesonide and fluticasone.

x DR. CHOWDHURY: Moving on with the next

section of the presentations. In this section

you\'re going to hear information regarding adverse

events that have been reported to the air system

for budesonide and fluticasone containing products.

These adverse events may have been reported by

patients, physicians, health professionals or the

companies themselves, and specifically they\'re

reporting of these adverse events to you, the

171

Pediatric Advisory Committee, as I mentioned

before, is monitored by the BPCA. It\'s only for

one year, so you\'ll hear a lot of information from

a series of presenters. So we\'ll have questions

for clarification and also discussions of the

question that has been posed to the Committee at

the end of the series of presentations.

So you will hear from four speakers this

morning. The first speaker is Dr. Peter Starke.

Dr. Peter Starke is a pediatrician and a medical

team leader in the Division of Pulmonary and

Allergy Drug Products. He has been with the Agency

since 2000. Dr. Starke will be summarizing the

regulatory history and the labeling changes and

will provide a perspective on the safety of these

drug products which include the orally inhaled and

intranasal budesonide and fluticasone propionate

drug products. So this will give you I think a

good background in context for the next set of

presentations that will focus on the summaries of

clinical trials as well as the adverse event

reports.

172

Dr. Peter Starke.

x DR. STARKE: Good morning. I\'m Dr. Peter

Starke. As you\'ve heard, I\'m a pediatrician and a

medical team leader in the Division of Pulmonary

and Allergy Drug Products. This morning I will

attempt to place the written request studies and

the adverse event information, particularly the

adverse event information that you\'re about to

hear, into some perspective.

Although you will hear about adverse

events with all the budesonide and fluticasone drug

products, we\'re specifically going to deal with

just the orally-inhaled and intranasal drug

products, and not the cutaneous drug products, at

least my talk.

I want to assure you that we\'ve reviewed

this information carefully and are comfortable with

the adverse events that you\'ll hear discussed, that

they\'re appropriately represented in the label for

both of these drug products. In addition, many of

these types of adverse events occur with other

orally-inhaled and intranasal corticosteroids and

173

those two, as appropriate, appear in the labels for

those drug products.

This is an outline of my talk. I\'ll set

the stage for the discussion with some background

on the burden or allergic rhinitis and asthma in

the United States. I\'ll then focus on asthma and

review what is considered appropriate and necessary

treatment for persistent asthma as defined by the

National Asthma Education and Prevention Program in

cooperation with the National Heart, Lung and Blood

Institute.

These guidelines for the diagnosis and

management of asthma were first published in the

early \'90s and then again in 1997, and again in

2002\. You see the URL for the website listed at

the bottom of the slides.

Then I\'ll go into some of the regulatory

history and labeling chronology. The labeling for

these drug products has changed dramatically over

the last 10 years and I\'ll show you a lot of what

has happened in that time period. We\'ll go over

the specific results of growth suppression studies

174

with both budesonide and fluticasone, covering the

orally inhaled and then later the intranasal drug

products, and then I\'ll touch on the status of the

current labeling for safety findings for these

products.

This slide shows you a little bit of the

burden of allergic and non-allergic rhinitis in the

United States today. Allergic rhinitis is a very

common disease and it represents significant

morbidity as you see shown. The figures you see

come from the 1998 Joint Task Force on Practice

Parameters in Allergy, Asthma and Immunology, and

I\'ll touch later on their recommendations for us of

corticosteroids in the treatment of allergic

rhinitis. I\'m not going to talk at all about non-allergic

rhinitis.

However, we\'ll focus a little bit more on

the burden of asthma. This information and the

information on the next several slides comes from

the National Information Survey which is conducted

annually by the National Center for Health

Statistics at the CDC, and this information can be

175

found on both the NHLBI and the CDC websites.

Asthma is a significant public health

concern in the United States. It\'s associated with

significant morbidity and mortality. In the United

States it\'s estimated that over 20 million persons

are affected including over 6 million children.

You see on the slide the associated emergency

department, hospitalization and deaths during 1999.

This slide represents the burden of asthma

in terms of the prevalence per thousand population

in the United States today. Again this comes from

the National Health Interview Survey, and you can

see that the questions on the survey changed after

a period of time, and these questions represent

slightly different questions after\--I can\'t see the

date from here, but something like 1999. Now, what

you see is a rise in prevalence in asthma over

time, starting in 1980 at about 31 per thousand,

increasing by 1996 to 54 per thousand, an increase

of about 74 percent.

Here you see the mortality rates for

asthma in the United States over approximately the

176

same time period. This again comes from the same

database. You can see that the ICD codes changed

slightly around the year 1999 so they represent

slightly different coding, but again give you a

good sense of the mortality rates and what you see

as an increase from 14.4 in 1980\--this is per

million\--to a peak of 21.9 million, and then a

decrease to about 16 million by the year 2000. So

the peak prevalence was in 1995.

What I\'ve shown you is that in the United

States this represents, asthma represents a huge

burden to individuals as well as to the health care

system, and while the prevalence of asthma has

increased and increased quite a bit since 1980, the

overall increase in mortality has not reflected the

same rate of rise as the increase in prevalence.

The mortality peaked in 1995 and is now declining,

and most practitioners feel that this is due to a

combination of advances and care that are

monitoring, patient education and the use of

controller medications including the use of

corticosteroids for persistent disease.

177

This slide represents a brief summary of

the medications used in clinical practice for the

treatment of asthma, and you see quick relief and

long-term controller medications listed. I\'ve

highlighted corticosteroids and want to place their

role into some\--as a controller therapy into some

perspective here. Originally the NAEPP guidelines

recommended the use of controller medications for

moderate and severe persistent asthma, but the

latest recommendations now state that

corticosteroids should be used for all forms of

persistent disease.

Now I\'m going to switch topics a little

bit and start to give you a sense of what\'s changed

in the labels over the last 10 years. All of these

drugs were approved during the 1980s and 1990s

including budesonide and fluticasone. There are a

number of years during which some significant

events occurred. The first was 1994. In that year

the Pediatric Labeling Rule took effect, and that

labeling rule did a number of things, but among the

things that it did was that it required sponsors of

178

approved products to examine the existing data in

the product label to determine whether the

pediatric use subsection should be updated, and

this prompted a number of pediatric efficacy

supplements and many of these products were

approved to lower age ranges down to about 4 to 6,

and subsequently some lower.

In that same year the FDA began to review

the labels for all orally-inhaled and intranasal

corticosteroids and made a number of changes over

time. They started doing it then, but over time

have made a number of changes with the additions to

the labels of adverse events as reported to the

companies and to MedWatch.

Now, in 1997 several important events

occurred. First the NAEPP expert panel issued

their second report and I\'ve discussed the results

of their recommendations already, and you see them

up here. Second major event was that a growth

suppression study was submitted to the Agency, and

this study was a one-year study with intranasal

budesonide. The dose that was used was the highest

179

approved dose of 336 micrograms a day, and it

showed a statistically significant growth

suppression effect, but no significant effect on

hypothalamic-pituitary-adrenal or HPA access

function.

In addition, other growth studies were

submitted and are published, but particularly they

were submitted, and for both orally-inhaled and

intranasal drug products, but particularly for the

orally inhaled, and with this information several

things occurred.

I\'m going to skip over what happened and

just talk briefly first of 1998, come back to the

allergic rhinitis, and the Joint Task Force for

Practice Parameters, in conjunction with the

American Academy of Allergy, Asthma and Immunology

recognized intranasal corticosteroids as the most

effective medication for the treatment of severe

allergic rhinitis.

Going back to asthma, because of the

growth studies that came in a Joint Advisory

Committee meeting was held. This was a Joint

180

Pulmonary Allergy and Metabolic and Endocrine

Disease Advisory Committee meeting, at which time

the results of the growth studies that had come

into the Agency were discussed. They did recommend

a number of labeling changes, and I\'ll show them to

you in the next several slides. That included

putting results of growth studies in the label, and

adding class labeling for risks for adverse events

to all labels for orally inhaled and intranasal

corticosteroid drug products.

In November of that year, in November of

1998, the FDA implemented these recommendations,

sent letters to each of the sponsors requesting

supplements with additional labeling. Now, this is

the labeling in two of three locations that was

added to the labels, and as I just started to say,

there are three locations on the label where

labeling was added. You see the first two, the

Precautions, general and the Adverse Reactions

sections, and under Precautions, pediatric use

section, a long paragraph was added.

I haven\'t shown you the whole paragraph.

181

I have it if you want to see it, but this is a

synopsis of what was said, which is that: Orally

inhaled or intranasal corticosteroids may cause a

reduction in growth velocity in pediatric patients.

The growth effect may occur in the absence of

laboratory evidence of HPA axis suppression. The

potential for \"catch up\" growth following

discontinuation of treatment was not addressed.

Growth should be monitored routinely in patients.

To minimize the systemic effects, each patient

should be titrated to his or her lowest effective

dose.

Now, through our evaluations of growth

studies, we\'ve come to understand a number of

important points about these studies. First, we

feel that growth suppression reflects systemic

exposure to the corticosteroid. This is likely to

be due to a direct bone effect on osteoclastic-osteoblastic

activity. That\'s a presumption that

I\'m saying. We believe it\'s a very sensitive

indicator of systemic effects, and therefore, the

potential to cause systemic toxicity. And that

182

effect may be generalized to adults as well as

children. In other words, the growth suppressive

effect, being an indicator of the potential for

toxicity is not specific to just the growth

population that\'s looked at in the studies.

I\'m showing you where a growth defect

study may be positive where an HPA axis study was

negative. Because of the way we want the

information, we request that these studies look at,

as accurately as possible, and characterize the

difference in growth rate in patients treated with

active and with control. Now, they\'re quite

technically difficult to perform, and I do want to

congratulate both drug companies for having growth

studies with the intranasal and the orally inhaled

drug products, and I\'m going to show the results

shortly.

I\'m not going to go into the details of

the technical difficulties with doing them and/or

assessing them, but keep in mind that these require

at least a year on treatment, height measurements

with stadiometry, and they must be performed during

183

the relatively level or flat growth phase,

generally between 3 and 9 or 10 years of age, after

the infant growth spurt and before the pubertal

growth spurt.

There are a number of limitations to

interpretation of these studies. They are not

designed to demonstrate reversibility with

continued use after a year or after stopping a

medication. They\'re not designed to evaluate the

effects on final adult height, and you cannot take

the growth effect and relate it at all to the

individual patient. For these reasons, they are

very difficult to interpret out of context of the

study itself.

All the studies were designed prior to

when we published a growth guidance in 2001, and no

two studies had the same design. Therefore, it\'s

quite difficult to do any kind of cross-study

comparison, and I won\'t attempt to do so.

So here\'s the growth study for inhaled

budesonide. This is the design of the growth

study. It used Pulmicort Respules. This is, by

184

the way, not in the label. What\'s in the label is

the growth results for the 12-week study that gave

the indication. This information, however, was

discussed at the 1998 Advisory Committee meeting,

and therefore I\'m showing it to you now.

This was a 12-month open label extension

of a 12-week double-blind study. The arms you see

with inhaled budesonide and nonsteroidal. There

were several analyses done for different age

groups, 9 months through 3 years and 4 through 8

years. Before I show you the results, I just want

to caution you about interpreting results for the 9

month to 3 year age range, where growth is not

linear and where one generally has to measure

length rather than statutory height, and this

introduces a large variable into these kinds of

studies.

So here are the results for the orally

inhaled budesonide. You see at the top the 4- to

8-year-olds, and below it the 9 through 3-year-olds. You

see also the budesonide and then the

nonsteroidal groups below it, and the height

185

changes over the year\--I\'m sorry, the growth rate

over a year. The delta is what I would point out

to you. That\'s the difference between the active

and control groups. A negative number implies a

growth rate effect, a positive growth rate effect.

So you see for the age range of 4 to 8 a growth

suppressive effect of half centimeter, and for the

lower age range, 1.8 centimeters. So there clearly

is some difference between the two, but again, it\'s

hard to interpret what that difference actually is.

This is the growth study using inhaled

fluticasone propionate, and I believe this is in

the labeling. This used the Flovent Rotadisk. It

was randomized, placebo-controlled one-year study

in prepubertal children. You see that two doses of

fluticasone propionate were used in this study, 50

and 100 micrograms twice daily.

There are the results. There was some

indication of a dose response in this study, and if

you look at the first two lines of the delta you

see the results compared to placebo for the 50 and

100 micrograms twice daily.

186

So just to continue and update from 1998

to 2004, the Advisory Committee recommendations

were implemented, as I\'ve shown you. I mentioned

already that we published a draft growth guidance

in 2001. Guidances represent the best thinking of

the Agency, but they do not require sponsors to

follow that thinking if they can show us some

alternative methodology.

The labels have been reviewed and updated

with new labeling supplements as they come in, with

post-marketing adverse events as reported. You\'ll

hear the pediatric exclusivity studies next.

They\'re updated with pediatric exclusivity studies

results as appropriate and with the results of

Phase IV growth studies as they come in.

Here are the results for the intranasal

budesonide and fluticasone growth studies, and you

see the moiety on the left, the dose, the N, the

growth rate over a year, the difference between

active and placebo and the 95 percent confidence

intervals when we have them. For convenience I put

on the slide the results of the beclomethasone

187

study that started this all off in 1997, and you

see only a very small effect for each of these two

drug products. But I just want to point out the

budesonide used the lowest approved dose;

fluticasone used the highest. We do recommend at

this point that sponsors use the highest approved

dose in these studies.

So the labeling status as of 2004. All

labels clearly describe the potential risks for

adverse events; HPA axis studies. We\'ve included

the class labeling. There are some minor

differences between various drug products in the

wording, but that\'s probably fine. Growth studies,

as they come in; and all the labels are being

reviewed and updated as new labeling supplements

are submitted.

Specific labeling for budesonide and

fluticasone is shown in this slide. Both the

orally inhaled and intranasal drug products for

both of these drugs have HPA axis growth and post-marketing

adverse events labeled. In addition\--and

this relatively new information, so I\'ve included

188

it separately\--budesonide\--and you saw the results

of the growth study. That study is now in the

label as of the last month or two. In addition, as

of the end of August, budesonide was relabeled as

Pregnancy Category B, and this is as the results of

information from three Swedish birth registries.

You see a representative of what Category B, one of

the requirements for Category B. It was changed

from Category C to Category B.

So in summary, asthma is a chronic

inflammatory disease of the airways. It represents

a huge burden to the health care system. While the

prevalence of asthma has increased since 1980, the

mortality rates increased, and then have declined,

although the overall mortality rate is higher now

than it was in 1980. Corticosteroids are

recommended as a primary controller therapy for

persistent asthma, all forms, and as the most

effective therapy for severe allergic rhinitis.

The types of adverse events that may be

expected with this class of compounds, namely

corticosteroids, have been well documented over the

189

years, and the FDA is continually reviewing and

updating the labeling as we get more and more

information about the individual drug products.

I\'ve shown you how the labels have changed

dramatically over the last 10 years with class

labeling. We really haven\'t gone into HPA axis

information, but you\'ll hear more about that in the

written request studies. I\'ve shown you about the

growth studies. You\'ll hear about the adverse

event data. At this point we believe that the

current labeling for these drugs is concurrent with

the latest safety data for these products.

I leave you with this quote from the NAEPP

guidelines, from the 2000 guidelines, which state

that: \"Inhaled corticosteroids improve health

outcomes for children with mild or moderate

persistent asthma,\" and obviously with severe, \"and

the potential but small risk of delayed growth is

well balanced by their effectiveness.\"

Thank you.

Now I\'m going to introduce to you Dr.

ShaAvhree Buckman. She is a pediatrician with the

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Division of Pediatrics. She has Ph.D. training in

molecular cell biology and pharmacology. She\'s

been a medical officer in the Division of

Pediatrics for the last two years. She will be

presenting on the clinical studies for budesonide

and fluticasone.

x DR. BUCKMAN: I can now say good

afternoon.

\[Laughter.\]

DR. BUCKMAN: I will be presenting a

summary of clinical trial data for fluticasone and

budesonide. As an overview this table describes

the various fluticasone dosage forms, the original

dates of approval and current pediatric approval

information. This table includes topical,

intranasal and orally inhaled products.

The most recent approval, as of May of

2004, was for Flovent HFA Meter Dose Inhaler. HFA

stands for hydrofluoroalkane, and this inhaler is

designed with a CFC-free propellant that is more

environmentally friendly.

This table describes the various

191

budesonide dosage forms which include orally

inhaled, intranasal and oral products. Because the

names of some of these products can become

confusing, the slide just shows some examples of

some of these products. The Advair Diskus, Flovent

Rotadisk and Pulmicort Turbuhaler are inhaled

powders. Pulmicort Respules are a solution for

inhalation used in conjunction with compressed air-driven

jet nebulizers. Also shown here is a

typical Flovent Metered Dose Inhaler which delivers

aerosolized drug, and Entocort, which is shown in

the corner, is indicated for oral use only in adult

patients who have Crohn\'s disease. We will not be

discussing this product during today\'s

presentation, but it is a budesonide containing

product. Also shown here are two nasal

preparations, Flonase as well as Rhinocort Aqua.

Seven dermatology and pulmonary studies

were requested for pediatric exclusivity for the

fluticasone moiety. Four studies were requested

for Cutivate, which is the dermatologic product.

One study was requested for Flonase, two studies

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for Flovent, and there was also requested an in

vitro study report as well as a population PK

report for Flovent.

First we will discuss the studies for

Cutivate. As background, Cutivate cream has been

approved for use in children 3 months of age and

older since June 17th of 1999. A written request

was issued for other fluticasone containing

formulations on June 25th of 1999. This written

request included three studies for Cutivate lotion

and one study for Cutivate ointment. Also as

background, an Advisory Committee was held in

October of 2003, which many of you may have

attended, that discussed the clinical risk

management of HPA axis suppression in children with

atopic dermatitis who are treated with topical

corticosteroids. Presently, only Cutivate cream is

indicated for pediatric use, not the ointment.

The current labeling for Cutivate cream

includes studies which were not requested for

pediatric exclusivity. 43 pediatric patients were

treated with Cutivate .05 percent cream for atopic

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dermatitis covering at least 35 percent of their

body surface area for four weeks. 2 out of the 43

patients had HPA axis suppression, and follow-up

testing was available for one of those two

patients, which demonstrated a normally responsive

HPA axis on follow up.

This study using Cutivate ointment was

requested for exclusivity. 35 pediatric patients

were treated with Cutivate ointment for atopic

dermatitis covering at least 35 percent of their

body surface area for three to four weeks.

Subnormal adrenal function was observed with

cosyntropin stimulation testing in 4 of the 35

patients. The recovery of adrenal function in

these patients was unknown and follow-up testing

was not performed. This information was

incorporated into the Pediatric Use subsection of

the labeling as shown here. It is important to

note that Cutivate ointment is not indicated for

pediatric use.

Now we will discuss the clinical studies

for Flonase, the intranasal product. This study

194

was described to you briefly by Dr. Starke in the

previous presentation, and it was not requested for

pediatric exclusivity. This was a one-year multi-center

placebo-controlled trial looking at

longitudinal growth of 150 children, ages 3 to 9

years with perennial allergic rhinitis.

The mean reduction in growth velocity

after one year of treatment with Flonase at 200

micrograms per day was estimated at .137

centimeters per year. HPA axis evaluation in these

patients showed no interpretable effects on urinary

free cortisol. And this study supported safety in

children at the maximum approved dose and twice the

daily dose typically used in patients at this age

group.

The recommendation was made for the

results of this one-year growth study to be

incorporated into labeling, and you can see where

this was incorporated.

This study for Flonase was requested for

pediatric exclusivity. It was a six-week,

multicenter, placebo controlled HPA axis study in

195

65 patients between the ages of 2 and 4 years with

allergic rhinitis. 12-hour urinary free cortisol

was used to evaluate the HPA axis. The results of

this study were deemed indeterminate due to

limitations in urine collection and wide variations

in baseline urinary free cortisol levels between

treatments groups. Therefore, no labeling change

resulted.

Now we will discuss clinical studies for

Flovent. We have discussed studies for Cutivate

and Flonase, and now we\'ll briefly touch on an in

vitro study report that was done for Flovent for

exclusivity.

Prior to starting the clinical program

with Flovent, the sponsor performed a comparison of

the particle size distribution by cascade impaction

for Flovent CFC Metered Dose Inhaler with and

without the use of various spacers as shown here.

The results appear to indicate that the in

vitro respirable particle content was similar

whether the metered dose inhaler was studied alone

or in combination with either of three different

196

spacers. However, the study was unable to evaluate

factors that would have been important to the in

vivo clinical setting, and this would include

variations such as variations in flow rates, delay

between actuation of a dose and actual inflow, how

long a mask was held over the nose and mouth of a

child, and therefore, result of this study were not

incorporated into labeling.

These studies for Flovent were requested

for pediatric exclusivity as well. Two 12-week

placebo controlled efficacy and safety studies were

performed in children with symptomatic asthma, who

were between 6 and 47 months of age. Detectible

plasma levels of fluticasone were seen in 13 of the

placebo treated patients. Therefore, it was

impossible to evaluate the actual extent of patient

exposure and made the interpretation of the PK/PD

relationship difficult to assess. The

interpretation of this study was that it was

impossible to determine whether the studies derived

an accurate estimate of either safety or efficacy,

and therefore, no labeling change resulted from

197

these studies.

Now we will discuss the clinical studies

for budesonide. Two studies were requested for

exclusivity. One was a safety study of budesonide

nebulizing solution for the treatment of asthma in

children 6 months to 1 year of age, and the second

was an HPA axis safety study of the budesonide

nasal spray in children between 2 and 6 years of

age.

First we will discuss the studies for

Rhinocort Aqua, the nasal spray. This was a 6-week

multicenter placebo controlled study to evaluate

the effect of Rhinocort Aqua on HPA axis in

patients with allergic rhinitis. 78 children were

studied between the ages of 2 and less than 6 years

of age. The HPA axis function was evaluated by

low-dose cosyntropin stimulated plasma cortisol

measurements at baseline and following six weeks of

treatment. The results of this study were deemed

indeterminate because of difficulties in

determining patient compliance, and no labeling

change resulted.

198

Now we will discuss a clinical study for

exclusivity using Pulmicort Respules. This was a

12-week randomized placebo-controlled study to

evaluate the safety of Pulmicort Respules at .5 and

1 milligram daily in pediatric patients with mild

to moderate asthma or recurrent persistent

wheezing. 141 patients were studied between the

ages of 6 and 12 months. The main safety concerns

that were evaluated were concern for HPA axis

suppression and suppression of linear growth.

Of the 141 patients that were randomized,

76 patients had an ACTH stimulation test at the

beginning and the end of the study. The mean

values of the three treatment groups did not

indicate any difference in adrenal responsiveness.

However, six patients with Pulmicort Respules and

one patient in the placebo group had post-ACTH

plasma cortisol levels that were below normal.

There was also noted in the bottom study a

dose-dependant decrease in growth velocity between

the placebo and budesonide treated groups. Also of

note, pneumonia was observed more frequently in

199

patients treated with Pulmicort Respules than

placebo. Three patients were noted in the

budesonide treated group who developed pneumonia

during this study.

These findings were incorporated into the

clinical pharmacology and precautions subsections

of the label show here. In summary, the studies

for pediatric exclusivity have resulted in labeling

changes for fluticasone and budesonide containing

products. Pediatric trials for fluticasone and

budesonide have identified important safety

concerns which have been incorporated into

labeling.

This concludes my presentation, and I

thank you for your attention.

The next presentation will be given by Dr.

Joyce Weaver, who is a Safety Evaluator in the

Division of Drug Risk Evaluation in the Office of

Drug Safety at the FDA. She will be presenting the

adverse events for budesonide and fluticasone.

x DR. WEAVER: Good afternoon. I\'m going to

be presenting both use data and information about

200

adverse events reported to the FDA\'s Adverse Event

Reporting System for budesonide and fluticasone.

First I\'ll talk about budesonide. The

total number of prescriptions dispensed for all

budesonide products increase from approximately 6

million in 2001 to 7.8 million in 2003 with

pediatric patients accounting for about 29 percent

of the total prescriptions. Rhinocort, the nasal

product, is the most commonly used budesonide

product, accounting for over half of the budesonide

prescriptions, and of those, 17 percent were for

pediatric patients.

The inhalation product, Pulmicort

Respules, represents most of the rest of the

prescriptions for budesonide. Over half of the

Pulmicort prescriptions are for pediatric patients.

Entocort represents a very small portion of

budesonide dispensed.

The FDA\'s Adverse Event Reporting System,

or AERS, contains about 2,800 adverse event reports

for all ages covering the lifetime of the

budesonide products. For the one-year period

201

following approval of pediatric exclusivity, AERS

contains 157 cases including 38 pediatric cases.

The pediatric cases did result in some serious

outcomes including one death.

For the pediatric cases reported to us in

the year after approval of exclusivity, we received

more reports for boys than for girls, and most

reports were received for children 2 to 5 years of

age, and most reports were received for the

inhalation product.

This slide shows the most commonly

reported events in the pediatric cases in the year

after the granting of exclusivity. Convulsions

were reported most. Additionally, a number of

events were reported that are indicative of

systemic absorption of budesonide. Seizures are

not an expected reaction with the use of

budesonide. And when we looked at the cases we did

not see a clear relationship between budesonide use

and the subsequent development of seizures. One

case was confounded by concomitant use of

theophylline, and that case did not include a

202

theophylline level.

Two cases were not confirmed by health

care professionals and the seizures were not well

described. One patient was receiving CNS

radiotherapy, and that same patient was receiving

another drug concomitantly that is labeled for

inducing seizures.

We have 17 cases showing possible systemic

steroid effects including growth retardation,

decreased blood cortisol, adrenal suppression and

Cushing\'s syndrome.

As I said, we did receive a report of a

death in the year following approval of

exclusivity, and this case was reported from within

the United States. It was a 3-year-old girl who

had received Pulmicort Respules for 3 months. She

stopped breathing, was transported to an emergency

room, and she died in the emergency room. An

autopsy was performed but not establish a cause of

death.

We conclude from our review of the events

reported to AERS for budesonide in the year

203

following approval of pediatric exclusivity that

first, most events, including systemic steroid

effects, are included in product labeling; and

second, the convulsions are not labeled, but we

didn\'t see a clear relationship to budesonide.

Now I\'ll go on to fluticasone. First,

this is use data for fluticasone cream and

ointment. Children account for about one third of

the prescriptions for these products.

This is for fluticasone nasal spray.

Prescriptions for nasal spray have remained fairly

consistent over the past two years, with about 15

million prescriptions in 2003, and pediatric

patients account for less than 10 percent of all

prescriptions for fluticasone nasal spray.

This slide shows information for inhaled

fluticasone. For inhaled fluticasone there are

about 7 million prescriptions in 2003, and there;s

been a downward trend over the past couple years.

pediatric patients account for about one quarter of

the prescriptions for the fluticasone oral

inhalation products.

204

Now, to Advair. We\'re looking at this one

separately. Advair\'s a combination of fluticasone

and a long-acting beta-2 agonist, salmeterol. use

of Advair has increased considerably over the past

few years. Advair accounted for 17 percent of

orally-inhaled steroid prescriptions in 2001. This

increased to 54 percent in 2003, with pediatric

patients accounting for 13 percent of total

prescriptions.

Looking at the adverse events reported for

all fluticasone containing products, AERS contains

about 4,600 adverse event reports for all ages

covering the lifetime of the fluticasone products.

For the one-year period following approval of

pediatric exclusivity, AERS contains about 2,100

cases, including 128 pediatric cases. The

pediatric cases did result in some serious

outcomes, including 5 deaths.

For the pediatric cases in AERS in the

year after approval of pediatric exclusivity, we

received most reports for children 6 to 11 years of

age, and most reports were received for the

205

combination fluticasone and salmeterol product,

Advair. You can see in the right-hand column, 82

of the cases that we received, 82 of the 128, were

for reported events for that combination product.

This slide shows the most commonly

reported events in the pediatric cases in the year

after the granting of pediatric exclusivity. We

looked at these cases and we found two issues.

emerging from this.

The first issue we found was systemic

steroid effects. There were 12 cases showing

systemic steroid effects, and I\'ll address this

issue in a couple minutes. The second issue in the

cases was worsening asthma symptoms with the use of

Advair. We had 22 such cases reported in the year

following the granting of exclusivity, including

four cases in which the patient died.

So first we will address the cases

reporting worsening asthma symptoms with the use of

Advair. And as I said, we received 22 of these

cases in that one-year period. In 10 cases serious

outcomes were reported, including four deaths. The

206

patients were 5 to 14 years of age. Race was not

reported in most cases. The time to onset of

symptoms ranged widely from the very first day the

Advair was used to after two years of use. And the

AERS cases do not show what the relative

contributions of underlying disease and the use of

Advair may be in the adverse event.

I\'ll present the four cases on which the

patients died. The first case is a case

originating from the United States. A 14-year-old

black male was prescribed Advair after an episode

of respiratory arrest. He had received Advair

Diskus for 2 years when he experienced an acute

asthma attack. He was transported to an emergency

room. When he arrived he was in full cardiac

arrest and he died. No autopsy was performed.

The second case also originated from the

United States. This is a 13-year-old white male

who had received Advair for about 6 months. He

experienced an asthma attack and he died. An

autopsy showed chronic bronchitis, hypertrophy of

bronchial muscle, infiltrate of eosinophils, mucus

207

plugging of smaller airways, areas of pneumonia and

air trapping.

The next case originated from outside the

United States. A 14-year-old asthmatic girl was

treated with salmeterol for an acute asthma attack.

When she did not respond quickly to the treatment

with salmeterol, treatment with a combined

salmeterol fluticasone product was started. About

2 hours after her first dose of the combination

product, the patient\'s condition worsened and she

died.

The final case is a case, once again from

the United States. A 13-year-old boy experienced

cardiac arrest and died after receiving Advair for

an unknown period of time. The report stated that

while talking to a friend on the phone, the boy

just stopped talking. An autopsy showed only lung

changes consistent with asthma.

You saw this slide before. I\'m showing

you this slide again to remind you that most of the

cases we received in the year after the granting of

exclusivity were received for the combination of

208

fluticasone and salmeterol product, Advair. And

once again, it was 82 of 128 cases. And while the

use of Advair has been increasing in children, we

don\'t think that the increased use explains the

increased reporting in pediatric patients for the

product.

This slide shows the pattern of reporting

of pediatric adverse events with Advair, and the

timing of important regulatory action and an

important labeling change for Advair. Going across

the bottom of the slide, each column is a quarter.

So we start with a quarter in 2000 and go up to the

first quarter of 2004. In January 2003 the FDA

released a talk paper discussing the cessation of a

salmeterol safety study, and the interim analysis

of that study suggested that salmeterol may result

in worse asthma outcomes. And in August 2003,

Advair received a boxed warning about the

possibility of worse asthma outcomes with

salmeterol. And as you can see, the spike in

reporting for Advair occurred around the time that

Advair received that boxed warning.

209

This slide just shows the boxed warning in

the Advair labeling, and again, the boxed warning

was incorporated into the labeling because of the

interim results of the safety study, not because of

the AERS cases. So that\'s the first issue with the

fluticasone containing products.

Now I\'ll address the other issue that we

found in the pediatric cases, and that second issue

is the systemic steroid effects with the use of

fluticasone containing products. We had 12 such

cases, including a case in which the patient died.

Now, to look at these cases a little more

closely, most of the cases occurred with inhaled

products. In one-half of the cases the patient was

receiving more than one source of steroids

concomitantly, and we had only one case that

reported a systemic effect with the use of a

product within labeled dose and without an

additional source of steroids on board.

As I said before, we did have a case with

an outcome of death. This case originated from

outside the United States and we don\'t have

210

clinical details about the case. An 8-year-old

girl, who used an unknown amount of a fluticasone

containing product for an unknown dose, unknown

period of time, developed adrenal crisis and died.

So what can we conclude from the cases

that we\'ve received for fluticasone containing

products in the year after the granting of

exclusivity? Most of the events reported are

included in the labeling, including systemic

steroid effects and including worsening asthma with

the use of salmeterol containing products. In the

AERS cases of asthma exacerbation with Advair, the

relative contribution of underlying disease and

Advair to the events is not known.

That concludes my presentation.

You\'ve already met Dr. Chowdhury, but I\'ll

introduce him again. Dr. Badrul Chowdhury is the

Director of the Division of Pulmonary and Allergy

Drug Products. He\'s been with the Agency since

1997\. He\'s an internist, an allergist and an

immunologist, and he\'ll be summarizing the

pediatric programs for fluticasone and budesonide

211

that were presented previously.

x DR. CHOWDHURY: Thank you for the

introduction, and I will very briefly summarize the

programs that were done for fluticasone and

budesonide containing drug products for allergic

rhinitis and asthma indications, which are the

nasal products and oral inhaled products. I\'ll go

through them so that you can really put the

presentations that you heard before, three of them,

into context of the whole drug development programs

and where we stand currently with the labeling

status of these drugs, particularly for children.

Asthma and allergic rhinitis, as you have

heard before, are common diseases, and in fact

they\'re pretty common in children and impose

significant burden on the health care system and

also on individuals who have these diseases. And

the prevalence of atopic diseases in general and

asthma has been studied in depth. The prevalence

of this disease is increasing, but recently, as yo

have heard before, the trends in death and

hospitalization are declining. And the various

212

factors which are contributing to this good outcome

of a serious disease, including availability and

use of various controller medications.

As you\'ve heard before, corticosteroids

currently are the primary controller therapy for

all grades of persistent asthma, and they\'re being

used, and their use is also being covered under

various guidelines. For allergic rhinitis, again,

corticosteroid is considered to be the most

effective therapy.

These drugs, of course as we know now, are

not completely free of adverse events. The topical

drugs are applied on the surface or the body, and

historically at one time they were considered to be

really surface acting and not systemically active,

but now we know that they are systemically active,

and has adverse events, which came back to the

systemic exposures, particularly those allergic to

suppression of the HPA axis and also other

metabolic effects. But the benefits of these are

appropriately labeled and overall the risk/benefit

supports the use of these drugs.

213

Now, I think we may have skipped a slide.

Yes. I will, on the slide, very briefly go through

the pediatric development of these drugs so that

you can put the studies that you have heard in the

context. Usually for asthma and allergic rhinitis

these drugs are developed for adults first, and

then the efficacy and safety goes down to the

pediatric patients usually be generating data and

by extrapolation, because we think the diseases are

same in adults and children and the effect of the

drug on the diseases are also the same.

Now, in going down in the age, one

important consideration is to identify appropriate

dose. Because this is surface active, therefore PK

is not a good marker for dose selection. They are

usually done through clinical studies, and for

these diseases, asthma and allergic rhinitis, it is

often quite difficult to design appropriate studies

with efficacy endpoint, but again, they are being

done to pick the right dose, and the aim here

being, both for adults and also for children, to

have a reasonably low effective and safe dose, and

214

then particularly for the children, show

established safety of that dose.

So safety is a key in going down in the

ages for these drugs, and safety assessment is done

in a variety of ways and you have heard some of

them. To summarize them here in the slide, we look

at clinical trials and monitor them for adverse

event, laboratory parameters, ECG findings, et

cetera, and then look at HPA axis in varieties of

ways, such as ACTH simulation test or look at

plasma cortisol and urinary cortisols.

And these, which means the clinical

studies and safety assessment of HPA axis are done

pre-approval. Then the growth study comes in,

process of linear growth, which really is a

surrogate of systemic effect, and they\'re usually

long studies, quite difficult to perform and

interpret, and they\'re usually done post-marketing

as a Phase IV. And then of course, after

marketing, we look at post-marketing adverse

events.

So the next three slides I\'ll quickly go

215

through these three aspects which is HPA axis

safety, linear growth and post-marketing adverse

events, and put some comments of mine on these

three areas.

You\'ve heard the pediatric studies which

was done for specificity presented, and typically

for asthma for both of these drugs, they were

efficacy studies. And the ages that we ask for for

efficacy study at the time we solicited request was

based on what we already knew and what we wanted to

know. For example, for budesonide, it was one year

and below because the drug was already at that time

approved a study for one year and above. For

fluticasone it was 4 years and below for the same

reason again, the drug was studied and indicated

for 4 years and above.

For allergic rhinitis the study was a 6-week study

primarily designed to look for safety,

which means all kind of safety, adverse events

reporting, clinical monitoring for adverse events,

and also HPA axis safety. I will not go through

the results of these. You\'ve already heard Dr.

216

Buckman present results. Some of them are

reflected in the label and some of them are not,

and we made the decisions on a case-by-case basis,

looking at the study, what we could come out from

the study in terms of what could go on the label,

and appropriate labels have been updated.

For assessment of systemic effects, as I

said before, it is done really by two ways. One is

assessment of HPA axis directly by either a

stimulation test or by measuring cortisols in the

plasma or urine, and these are done pre-approval,

and for these drugs, generally they\'re negative,

but again, not all. If you look across the drug

classes, the product labels are quite different and

they reflect the studies in the product labels.

And the growth study which, as you\'ve

heard before, you\'re studying the systemic effect

and systemic toxicity perhaps, was also done for

these drugs, and their effects are quite

numerically small, and they\'re again reflected in

the product label.

On the post-marketing side for adverse

217

events for these drugs, the large number of adverse

events which is not unexpected, is systemic

corticosteroid effects or effects related to

suppression of HPA axis. These are expected and

these are labeled, and these were seen in the HPA

axis studies and also in the post-marketing

studies, and the current label reflects these

potential systemic adverse events.

The worst thing for asthma with Advair is

something which is noted in the product label quite

prominently, and whether it is coming from

salmeterol contributing or whether it is coming

from the fact that Advair is typically used for

patients who have more severe asthma is currently

unknown. One can speculate it can be either/or.

Perhaps the patients with asthma who are more

severe are put on Advair; therefore, having

worsening of asthma is not necessarily very

unexpected. And we also know recently that

continued use of beta agonist, specifically

salmeterol, can worsen asthma. Again, these are

known adverse events that we know of now and is

218

adequately reflected in the product label.

To summarize this whole pediatric studies

that we have, the safety concerns would be use of

oral inhaled and intranasal corticosteroids,

specifically budesonide and fluticasone which we

are discussing today, are well characterized, so we

know what the adverse events of these drugs are,

and they\'re adequately described in the product

label. The new data that we have obtained under

pediatric initiatives in post-marketing adverse

events are reassuring because we are not really

seeing anything new which is totally unexpected.

What we are seeing is what we expected to see, and

they\'re not extremely, extremely common, and these

are again adequately reflected on the product

label.

So this risk/benefit assessment, these

drugs of course have some adverse events, have some

risk, and we think it is adequately reflected on

the product label, and overall benefit of the drug

is justified and well balanced with a safety and

risk assessment of these drugs.

219

Thank you very much, and with this, I\'ll

stop.

DR. CHESNEY: Thank you very much to all

the speakers. A very, very comprehensive review of

these two products. Questions from the panel?

Yes, Deborah first, and then Dr. Fant.

MS. DOKKEN: I want to ask this question

just because I have to leave in a few minutes, but

as a lay person I have been scrambling to keep up

during this discussion. And one of the things that

struck me despite the overall conclusion that the

results were reassuring, was of course both the

rise in the use of Advair and the worsening of

asthma, those adverse events reports. But then the

fact that the labeling was changed, and somewhat

for clarification for myself as a newcomer to this

Committee, but also as I guess a consumer concern,

when the labeling was changed due to the adverse

events, would that be a trigger for the MedGuides

that we talked about yesterday? I guess I think in

particular because of the prevalence of asthma and

the growing numbers, but also I think those of us

220

who either have children who have asthma or know

families, there are a number of families who are

very active if their children have asthma, and are

good advocates. So they would be cognizant and

would take note of information if it was made

available to them in a way. So that\'s my question

about the MedGuides. Would those go hand in hand

or subsequently with a change in labeling?

DR. MURPHY: A Medguide is not tied any

particular change. It is something that is, the

decision that is arrived at depending on the

circumstance, so it is an independent decision.

Badrul, do you want to talk about any

products that have MedGuides?

DR. CHOWDHURY: I don\'t want to comment to

the MedGuide here. The issue is that you are

right, that when a box warning or some significant

labeling or a doctor letter goes out, which had

happened for salmeterol-containing products. It is

quite likely that will increase the adverse event

reporting by physicians or by patients.

And about the use of Advair and use of

221

Advair in children, I mean it is somewhat high, and

whether it is a good or a bad thing is very

difficult to actually conclude and say. You\'ve

seen for pediatric requests we did not particularly

request studies for Advair. We requested study for

fluticasone and not for the combination product,

because we do not think that use of Advair in very

young children is something which should be really

routine because there are very difficult to titrate

the combination products, you actually have one

product. And we thought in children it\'s not

really very appropriate drug to use. But we also

know that Advair is very, very commonly used, and

is actually quite commonly used in children and

there are three dose strengths available. And

often physicians and patients may not go down on

the dose when their asthma is controlled.

So I think we have put down enough

information in the label, and also there have been

some dear doctor letters and some of the public

forums where we have spoken about it, and we

discourage the use of particularly high dose Advair

222

if it\'s not necessary, and also not to use the

combination products in very young children where

you want to titrate the dose. So I think it is

adequately recognized.

But again, going too much on the other

side is also a risk because that can lead to

decreased use of this quite effective controller

therapy. If you look at the U.S., it\'s

approximately thought about that about half of the

patients who should be on controller therapy

actually are on controller therapy. If you look at

Europe, it\'s actually much more high. So even in

the U.S. with continued education, continued

awareness, the use of controller therapy is not

where I think where experts want. So in that

context, putting too much of a cautionary note may

actually lead the pendulum swinging in the opposite

directions. This is a tight balance, and I mean

you can give European and they like to hear that,

but we think that balance is quite well struck.

MS. DOKKEN: Just one comment. I mean I

think we talked a lot in the last two days about

223

that issue of balance. And I guess my own belief

is that there may be a way to inform and empower

families so that what I talked about yesterday, so

that they are aware of the risks and can truly be

part of the risk/benefit analysis. And I

ultimately don\'t think that that will lead to

panic, and you know, restricting use of medications

from patients who need them. But I think it could

lead to more informed decision making.

But also, families are part of the

monitoring system, and if they\'re not always aware

of what they\'re looking for, then they can\'t be

very effective monitors.

DR. CHOWDHURY: It is a very good

suggestion, and thank you for the suggestion, and

we really take the suggestions very seriously from

the public meetings. Just to let you know that

when there are public advocacy groups and also

family groups, one of them which is pretty active

in the family field is Mothers of Asthmatics. And

they\'re actually very much aware of what has been

happening with the FDA. And many of those

224

meetings, they actually come, and they make

presentations. So they are actually very much in

line, and the persons who head up that group, we

have lot of discussions with them, and as far as we

could tell, they\'re pretty satisfied where the

balance is right now, but again, your suggestion is

very well taken, and thank you for that.

DR. CHESNEY: Dr. Fant and then Dr.

Nelson.

DR. FANT: Just a couple of questions to

fill in a couple of gaps on background for me.

One, is there any data that points to\--the decline

in mortality has been commented on a couple of

times. Does the data suggest that the use of the

corticosteroids contributes to that, or\--I\'ll let

you answer that and then I\'ll just ask my second

question after that.

DR. STARKE: The data on mortality comes

from coding, primary coding for hospital discharge

or death, and that\'s collected annually by the CDC.

So this data, it\'s difficult to extrapolate any or

interpret what the meaning of that data is compared

225

to the use of controller therapy. I don\'t think

you can make any specific comments on the

relationship.

DR. FANT: We know from studies that the

use of corticosteroids is the most effective

controller or one of the most effective

controllers, but we don\'t know for sure if it is

the major contributor to the decline in mortality;

is that correct?

DR. STARKE: That\'s correct.

DR. CHOWDHURY: Let me make a comment

here. I mean usually\--I mean you can\'t really make

a conclusion regarding an intervention and outcome

which is mortality because in aspect it\'s still a

very heavy event, so it\'s actually very, very

difficult to make that conclusion. It\'s probably a

combination of all. But if we take surrogates, for

example, which is exacerbations of asthma, or

hospitalizations because of asthma, which usually

are surrogates of even worst outcomes, I mean

usually with controller therapy all of these

actually goes down, and I would not really pick out

226

one class of drug over the other as more

contributing than the other.

DR. FANT: No, no. I\'m not trying to pick

out any. I\'m just trying to get a better sense to

help me sort of understand the complexity of this

in weighing\--

DR. CHOWDHURY: It is, and I think one can

reasonably say\--Dr. Starke mentioned that the

better outcome that you\'re seeing is a combination

of a lot of things, including better views of

controller therapy. But other factors are also

playing a role.

DR. FANT: My second question relates to

Advair specifically and the adverse events that

seem to be associated with that. Is there any data

or information that looks at similar events that

occurred when similar\--the same two classes of

drugs were used separately but in combination? Is

it something that seems to be unique to Advair? Is

it something that clearly seems to be an

interaction between a long-acting beta agonist and

steroids? Does it seem to be a beta agonist issue

227

only? Do we have any information that may help

kind of provide hints and what may be the

underlying problem, if there is one?

DR. CHOWDHURY: That\'s a very tricky

question and maybe even a very tricky study to do,

and the bottom line is the data is not available.

And there are no studies long term looking at

outcomes. What we have long term is the use of a

beta agonist alone versus placebo, and you have

probably heard about that study. But there is

nothing such available comparing an Advair arm

concomitantly taken, so that data is not there.

DR. FANT: Or adverse events that have

been reported and in the narrative certain things

get blamed, like\--

DR. CHOWDHURY: Adverse events are there

with fluticasone, adverse events are there with

Advair, and as you have seen, with Advair the

adverse events are just more, and they\'re higher,

they\'re more serious. So that signal is there.

But, I mean, there is no controlled studies that

can go into the explanation whether it is from

228

Advair or whether it\'s something else confounding

which is contributing to that. Those controlled

studies are not available.

I don\'t think it really is a very useful

information either because it\'s quite well known

that Advair is taken by patients who are more sick

and, therefore, having an adverse outcome coming

out of a sicker patient population is not a big

surprise, and also with the new beta agonist study

we know that routine use of beta agonist leads to

worsening asthma and increased death. And that\'s

already in the product labeling for Salmeterol and

also for Advair. So the information already is in

a way known that routine use of beta agonist\--

DR. FANT: But if you have a sicker

patient who\'s getting treated with a drug that puts

him at increased risk, if there\'s an interaction

effect, that certainly is a patient I would really

want to\--really would not want to elevate that risk

anymore.

DR. CHOWDHURY: Again, there is\--

DR. FANT: You know, I\'m not\--

229

DR. CHOWDHURY: No, these are important

discussions to have because it\'s actually quite

important for, I think, everybody in the country to

be aware of this. It is an increased risk of

adverse outcome, but the risk is actually very,

very small. If you look at the black box language

which was put up very briefly, the number of deaths

is like in two digits out of a 16,000 patient

population. This is a very small signal. And I

don\'t think really for the small signal one should

not use the drug. The drug is very effective.

There\'s no question about that. And it\'s also

pretty safe. And the signal, which is a serious

signal, is not very common. So I don\'t think\--it

is really, again, a balance. The signal is really

coming out of a very small number of patients. And

the more studies going through to the NIH

initiatives trying to identify who those patients

may be who actually would have the risk, that has

been partly identified with the short-acting beta

agonist. The studies which have been published\--there\'s a

large study which shows the biomarkers

230

associated with that. And in the future, there

will be studies coming out trying to identify

patients who are at risk.

DR. FANT: Thank you.

DR. CHESNEY: Dr. Nelson?

DR. NELSON: I\'d just like to highlight

two issues that are raised by the Flovent

exclusivity studies, which I realize may be

impossible to talk about today but might merit

further conversation in the future.

One is the choice of control group. Those

particular trials included children who had been

receiving symptomatic treatment two times a week

which meets NHLBI criteria for the provision of

anti-inflammatory; but, nevertheless, a third of

them were randomized to placebo. So the question

would be: What is the current thinking about

appropriate control groups when you have actually

treatment guidelines that, in fact, a third of the

population did not receive?

The second point is this was the study

that also then had misallocation of study drug, and

231

so you end up with the irony\--and they also were

then granted exclusivity, and I don\'t know if

that\'s because the written request was not ironclad

enough to not give them exclusivity, or if, in

fact, it was felt that they weren\'t to blame for

the misallocation. But either way\--and I realize

each of these issues merit debate in their own

right, but if you sequence them together in the

most unfavorable light\--which is not necessarily

what I\'m going to argue for, but some might\--you

have a study that withheld effective medication

from a third of the kids in the study that didn\'t

get done right, resulted in useless data, and they

got the money anyway.

DR. CHOWDHURY: Let me take the questions

very, very briefly, because you told it very

correctly, these are really larger discussions.

The first issue is regarding placebo in

these trials. There are two things to consider.

They\'re actually placebo-controlled but not really

without any drug treatment arm. These patients can

take rescue medications as necessary and actually

232

can drop out of the studies if their asthma becomes

uncontrolled.

The second thing is that in a short-term

study taking off control therapy has not been shown

to affect asthma in the longer term. There\'s

CAM(?) studies out there going for quite some time,

which does not show that if you do not use a

control therapy for a short term, then the lung

function of those children is reversibly damaged.

So there is some gain to obtained from

some study, and withdrawing control therapy for a

short time period with the proper rescue

medications available is, again, a reasonable

risk/benefit for the study.

And the second issue regarding, I would

say, misallocation, whatever the reason being, of

having drug in the placebo, is not something that I

would\--GSK did not want that to happen, neither did

we, and the reason it happened is not really very

clear. And you are totally right. Because of

this, drug levels in the plasma, the studies were

not useful. And whether exclusivity should have

233

been granted or not, I will defer to Dr. Murphy on

that. It\'s a tricky issue.

DR. CHESNEY: Before Dianne comments, we

may be looking at the same study. I can\'t tell.

But Dr. Buckman\'s Slide 18, which was the\--is that

the same study?\--where they found levels in the

placebo and really couldn\'t come up with any

conclusions at all, and your first thought is: Why

was exclusivity granted when this study really on

paper doesn\'t look very good?

Dianne?

DR. MURPHY: Between ShaAvhree and I, our

memories are not clear enough to give you a factual

answer. So we think it\'s because we weren\'t\--you

know, but one of the problems with exclusivity is

that there\'s a short-term\--we have to determine the

exclusivity before the complete analysis is

performed. And we will get back to you. I think

this is one of the action items we need to get back

to this committee at the next meeting about why was

exclusivity granted in this situation. But our

hazy combined recall\--maybe Peter can help us. We

234

didn\'t know at this point.

DR. CHOWDHURY: Let me also chime in on

this. The studies for pediatric exclusivity comes

into a supplement to the NDA, and we have a time

clock for reviewing the studies because it involves

a lot of analysis, often going into the data and

all, and the time frame is six months for pediatric

studies. And exclusivity is granted or denied very

early on.

DR. MURPHY: It\'s within 90 days, so\--

DR. CHOWDHURY: So when the application

comes in, we file the application, and then the

exclusivity is granted based on whether the study

was done fulfilling the criteria set forth in the

written request. And the analysis goes on. So, I

mean, one is happening before the other.

DR. MURPHY: What is determined, just

again, for what we can tell you, is: Did they do

the studies that we asked them to do? And so when

the division comes to the Exclusivity Board, they

bring the written request and basically a check

item. They go through every item. Did they do 2,

235

randomize? You know, now, you could say it wasn\'t

well controlled, but the division answers as best

it can without having completed the analysis. And,

therefore, the finding of some of these things,

particularly some of the compliance issues and the

scientific investigation issues are not available

frequently until literally towards the end of the

analysis.

DR. NELSON: Just a quick comment. I can

appreciate the systems issues in my approach

working in an ICU, this is all CQI systems issues.

And if, in fact, it\'s the simple existence of a 3-month

difference between one decision versus

another and the data gets analyzed, then maybe we

need to look at that as an issue. But I think

certainly the intent of the exclusivity is to have

interpretable data. And maybe there needs to be a

fix. Whether that\'s a regulatory fix or a

legislative fix\--I realize you can\'t advocate for

legislative fixes, but it just seems to me a gap

that ought to be examined, and this would, in my

mind, be a sentinel event. If I had something

236

happen in my ICU, we would look at it as a sentinel

event and say, How do we close that gap?

DR. MURPHY: Actually, it used to be worse

because we didn\'t have all of them on six months.

And so the system was even more likely to have a

problem, is what I was trying to say. We were

hoping by having the six months versus the 90 days

that we would have less events, but clearly we

still have them.

DR. STARKE: Let me see\--I\'ll try to

answer the question as best as I can. I was the

medical officer who reviewed the studies and

presented to the Pediatric Exclusivity Board at the

time. If I\'m not mistaken\--I\'d have to go back and

look, but I believe it was a 10-month clock for

this that had preceded that. And the Pediatric

Exclusivity Board met early in the analysis

process. It was only later in the process that we

found these events had occurred in the

biopharmaceutical portion of the study.

DR. MURPHY: That\'s what I was referring

to. Until the recent legislation, there were even

237

longer dates. Thanks for clarifying that.

DR. O\'FALLON: Well, who is responsible

for doing those biochemical, whatever, analyses?

Is that supposed to be the investigator who put\--the company

that gives it to you and you\'re

supposed to look at it? Or is the FDA supposed to

run it?

DR. CHOWDHURY: You\'re asking who is

responsible for analysis of the results? It is the

company or the company\'s contractor who is doing

the study is supposed to do the analysis. And I\'m

pretty sure when the submission of the (?) was

made, the company knew that there was some problem

with placebo arms having active drug.

DR. O\'FALLON: And they didn\'t share that

information, they didn\'t give that to you?

DR. CHOWDHURY: It was there in the whole

submission. That\'s the reason we know about it,

and we did not approve the application. But if you

go back to what was discussed earlier, the

exclusivity determination is made very early on in

the chronology of events. And in that time, that

238

formulation, that placebo had drug. I mean, it was

not identified, and even if it was identified, you

actually had to look at the cause of what happened

and can still the study be salvaged anyway? And

that takes time. And because of that, we have this

six months versus ten months of clock to go through

all of these. And by the time exclusivity is

granted, it\'s basically based on was the study done

based on what was asked. Analysis just cannot

happen at that time because it requires time.

It is a system that, Dr. Nelson, as you

pointed out, really as a\--noting as a case.

DR. CHESNEY: The newest legislation is

for six months, not 90 days anymore?

DR. MURPHY: No, for the review. All

pediatric applications now are considered six-month

reviews.

DR. CHESNEY: Any other questions or

comments from the committee?

\[No response.\]

DR. CHESNEY: Let\'s turn to the question

then which we have been asked specifically to

239

address. Based on the presentations you have heard

today regarding drugs containing fluticasone or

budesonide, do you have any concerns about the use

of these drug products as labeled? If you do have

concerns, could you please raise your hand?

\[A show of hands.\]

DR. CHESNEY: I believe with the members

of the committee who are still here we have a

consensus that we do not have any concerns about

the use of these drug products as labeled based on

the very comprehensive reviews you\'ve presented to

us.

x All right. Well, let me then just try to

summarize what we have\--the discussions we

participated in this morning. The first had to do

with the review of the Subpart D Pediatric Ethics

Subcommittee summary, which was presented by Dr.

Nelson, with some very good discussion by the

committee. The committee had two additional

recommendations for the summary, the first of which

was to assure that no stimulants were provided

within some reasonable period of time before the

240

study was initiated, and the second was that a

comment be added to the consent form regarding the

available NIMH information that only four of 3,000

patients who have had MRIs had any significant

findings. Do I have that correct? Thank you.

Second, the committee understands that

there will be no further reporting required for the

four drug products presented mid-morning:

ofloxacin, alendronate, fludarabine, and

desloratadine.

The third point, there was significant

discussion regarding adverse event reporting for

drugs either approved or not approved for use in

children, and I think not new to this particular

committee hearing is the perception that we need

better databases; particularly we need better

databases that involve children. We also need

better denominator data that involve children, and

I don\'t think there was a lot of discussion

reviewing the potential need for active

surveillance for better documentation of adverse

events.

241

And just to emphasize again the importance

of having information from controlled clinical

trials in order to better assess adverse events.

Finally, on the last issue with regard to

budesonide and fluticasone, we were presented with

very comprehensive data regarding the linear growth

assessments, the HPA axis suppression, and

regarding postmarketing adverse event reporting.

And the committee\--first of all, there was a

recommendation that a MedGuide be provided for

pediatric family caregivers with respect to the new

labeling for Salmeterol and Advair label changes.

And, secondly, a concern which was discussed in

some detail today and yesterday, which I think

overall we could say has to do with the quality of

the studies requested for exclusivity, and I think

we understand the process, but as Dr. Nelson

pointed out, what we\'ve come up against may be

totally a process issue. And we understand better

the reasons for why some of\--why exclusivity is

granted when the clinical trials may not

necessarily seem to us to have been designed as

242

well as they might have and the results turn out

not to be very helpful.

Any other summary comments that I have

neglected with respect to the committee?

\[No response.\]

DR. CHESNEY: And, finally, in response to

the specific question we were asked to address, we

do not have concerns about the use of these drug

products with respect to budesonide and fluticasone

as currently labeled.

And, finally, just to thank particularly

the FDA speakers who spoke this morning. I just

have this fantasy that you rehearse these things

for days and days beforehand and that somebody

oversees them and tells you exactly when were going

to have mental questions because you address them.

At least as soon as they come in my mind, you

address the issues. So we\'re just extremely

grateful for how much you respect our time and for

how comprehensively and well you review the topic.

That is just very much appreciated.

Thank you also to Jan Johannessen, who has

243

done an incredible job of keeping everybody on

track for the past week. This has certainly been a

long trek, more so for you than for us for sure.

To thank all the panel members who are

still here who raised always very stimulating and

thoughtful questions from my perspective.

To thank Skip for chairing the first-ever

Pediatric Ethics Subcommittee.

To thank Dianne, as always, for overseeing

this whole operation; Solomon for his always

comprehensive presentations.

And, finally, I think this is Dr. Ebert\'s

last meeting and Dr. Maldonado\'s last meeting. Am

I correct? And anybody else?

\[No response.\]

DR. CHESNEY: So I think they both got

recognized at the June meeting of the old

committee, but in any case, thank you from my

perspective for coming back and joining us for this

meeting and for being a part of this committee.

I\'ll let Dr. Murphy have a follow-up\--oh,

one more thing. Before we finish officially, I

244

wondered if the committee could stay for just one

minute. We had suggested potentially at the June

meeting writing up some of the\--well, I\'ll address

it right now\--some of the issues that have come up

over the years, and I am here to tell you that Dr.

Laurel Leslie, who I understand in the pediatric

community is known as a writing machine, has

already written up a potential manuscript based on

her review of what happened yesterday. And she\'s

very interested in finalizing this and submitting

it to a journal, and I would appreciate your

thoughts, which we could do after we officially

finish the meeting, as to who should be included in

that, what journal you might consider that that

should go into. She\'s thinking about Pediatrics,

but I wonder, as we discussed in June, if there

might be a more comprehensive audience if she

thought about something like JAMA. But if you

wouldn\'t mind at the end in a few minutes just

giving me your thoughts about that, I would be very

appreciative.

So, Dr. Murphy, to finalize?

245

DR. MURPHY: How many ways can I say thank

you? That really ought to be the question. I know

you guys have been\--ladies and gentlemen, excuse

me, have been through a grueling four or five days.

I think what was interesting to hear this

discussion this afternoon, which very much

paralleled the questions that came up yesterday

with the antidepressants where you have, you know,

an adverse event that\'s part of the disease, if you

will, and how you dissect that out and when do you

not say the labeling is sufficient, because the

division is certainly\--they also do the labeling.

So I think it\'s a real compliment to you

and the division that this committee, which has

been trained, mandated, and working on labeling,

you guys have done a good job. So I want to really

comment. I wasn\'t sure what they\'d say. Again, we

look very much forward to the ongoing activities,

and particularly, Dr. Nelson, to the immense amount

of work that you put into condensing that entire

day\'s ethical discussion and synthesizing it so

well for this group that they had as few questions

246

and recommendations that they did, and the ones

that they had were very thoughtful and very good.

I just look forward to working with you guys in the

future.

Thank you.

DR. CHESNEY: And is my understanding

correct that our next meeting is a week from today?

Is that\--

\[Laughter.\]

DR. MURPHY: I wanted to say one last

thing. Jan had no idea he was getting two

committees. He thought he was getting one. And we

are trying to make it so that you all don\'t have to

have residences here in Washington, though I

understand some universities do that. But we\'ll

try to be reasonable in our future requests on your

time.

Thank you.

\[Whereupon, at 1:10 p.m., the meeting was

adjourned.\]

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