A Matter of Record
October 30, 2017 | Author: Anonymous | Category: N/A
Short Description
of the questions that I hope. 4. Janet Evans-Watkins 03-09-15 FDA DODAC PM Session _Revised 04-22-15_ matter ......
Description
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1
FOOD AND DRUG ADMINISTRATION
2
CENTER FOR DRUG EVALUATION AND RESEARCH
3 4 5 6
DERMATOLOGIC AND OPHTHALMIC DRUGS
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ADVISORY COMMITTEE (DODAC)
8 9 10
Monday, March 9, 2015
11 12
Afternoon Session
13 14
1:06 p.m. to 5:06 p.m.
15 16 17 18
FDA White Oak Campus
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White Oak Conference Center
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Building 31, The Great Room
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Silver Spring, Maryland
22
A Matter of Record (301) 890-4188
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Meeting Roster
1 2
ACTING DESIGNATED FEDERAL OFFICER (Non-Voting)
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Jennifer Shepherd, RPh.
4
Division of Advisory Committee and Consultant
5
Management
6
Office of Executive Programs, CDER, FDA
7 8
DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY
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COMMITTEE MEMBER (Voting)
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Lynn A. Drake, MD
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(Chairperson)
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Lecturer
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Harvard Medical School
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Department of Dermatology
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Massachusetts General Hospital
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Boston, Massachusetts
17 18
Mary E. Maloney, MD
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Professor of Medicine
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Division of Dermatology
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UMass Memorial Medical Center
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Worcester, Massachusetts
A Matter of Record (301) 890-4188
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1
DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY
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COMMITTEE MEMBER (Non-Voting)
3
Gavin R. Corcoran, MD, FACP
4
(Industry Representative)
5
Chief Medical Officer
6
Actavis plc
7
Jersey City, New Jersey
8 9
TEMPORARY MEMBERS (Voting)
10
Mural Alam, MD, MSCI
11
(Morning Session Only)
12
Professor of Dermatology, Otolaryngology, and
13
Surgery
14
Chief, Section of Cutaneous and Aesthetic Surgery
15
Department of Dermatology
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Northwestern University
17
Chicago, Illinois
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TEMPORARY MEMBERS (Voting) (cont.)
2
Wilma F. Bergfeld, MD, FAAD
3
Professor of Dermatology and Pathology
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Senior Dermatologist & Co Director
5
Dermatopathology
6
Departments Of Dermatology and Pathology
7
Cleveland Clinic
8
Cleveland, Ohio
9 10
Warren B. Bilker, PhD
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Professor of Biostatistics
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Department of Biostatistics and Epidemiology
13
Perelman School of Medicine
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University of Pennsylvania
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Philadelphia, Pennsylvania
16 17
Danielle Boyce, MPH
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(Patient Representative)
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(Afternoon Session Only)
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Philadelphia, Pennsylvania
21 22
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TEMPORARY MEMBERS (Voting) (cont.)
2
Erica Brittain, PhD
3
Mathematical Statistician and Deputy Branch Chief
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Biostatistics Research Branch
5
National Institute of Allergy and Infectious
6
Disease (NIAID)
7
National Institutes of Health (NIH)
8
Bethesda, Maryland
9 10
Julie Cantatore-Francis, MD
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(Afternoon Session Only)
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Dermatologist/Pediatric Dermatologist
13
Dermatology Physicians of Connecticut
14
Norwalk, CT/Shelton, CT
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Voluntary Faculty, Department of Dermatology
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Yale New Haven Hospital
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New Haven, Connecticut
18 19
Cynthia Chauhan
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(Patient Representative)
21
(Morning Session Only)
22
Wichita, Kansas
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1
TEMPORARY MEMBERS (Voting) (cont.)
2
Bernard A. Cohen, MD
3
(Afternoon Session Only)
4
Professor, Pediatrics and Dermatology
5
Johns Hopkins University School of Medicine
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Baltimore, Maryland
7 8
John J. DiGiovanna, MD
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Staff Clinician
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Dermatology Branch
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Center for Cancer Research
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National Cancer Institute (NCI), NIH
13
Bethesda, Maryland
14 15
Anthony A. Gaspari, MD
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Professor, Department of Dermatology and
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Microbiology/Immunology
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University of Maryland Baltimore
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Baltimore, Maryland
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TEMPORARY MEMBERS (Voting) (cont.)
2
Brian Green, DO, FAAD
3
(Afternoon Session Only)
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MAJ, MC, USA
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Staff Dermatologist
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Chief, Pediatric Dermatology
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Associate Program Director
8
National Capital Consortium Dermatology
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Residency
10
Walter Reed National Military Medical Center
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Bethesda, Maryland
12 13
Kimberly A. Horii, MD
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(Afternoon Session Only)
15
Associate Professor of Pediatrics
16
University of Missouri, Kansas City
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Children's Mercy Hospital Division of Dermatology
18
Kansas City, Missouri
19 20 21 22
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1
TEMPORARY MEMBERS (Voting) (cont.)
2
Ken Katz, MD, MSc, MCSE
3
(Afternoon Session Only)
4
Dermatologist
5
Kaiser Permanente
6
Pleasanton, California
7 8
Loretta Kopelman, PhD
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(Afternoon Session Only)
10
Professor Emeritus
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Department of Bioethics & Interdisciplinary Studies
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Brody School of Medicine
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East Carolina University
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Greenville, North Carolina
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Professor, Practice of Family Medicine and
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Faculty Affiliate, Kennedy Institute of Ethics
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Georgetown University
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Washington, District of Columbia
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TEMPORARY MEMBERS (Voting) (cont.)
2
Alan Matarasso, MD, FACS
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(Morning Session Only)
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Private Practice
5
Clinical Professor of Plastic Surgery
6
Albert Einstein College of Medicine
7
New York, New York
8 9
Delora L. Mount, MD, FACS
10
(Morning Session Only)
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Associate Professor of Surgery, Pediatrics and
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Neurological Surgery
13
Division of Plastic Surgery
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University of Wisconsin School of Medicine and
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Public Health
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Madison, Wisconsin
17 18
Vesna Mrzljak, MD
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(Morning Session Only)
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Otolaryngologist in Private Practice
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Alexandria, Virginia
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TEMPORARY MEMBERS (Voting) (cont.)
2
Robert X. Murphy, Jr., MD, MS, CPE
3
(Morning Session Only)
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Associate CMO
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Attending Plastic Surgeon
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Lehigh Valley Health Network
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Professor of Surgery
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Morsani College of Medicine
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Allentown, Pennsylvania
10 11
Lisa A. Orloff, MD, FACS
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(Morning Session Only)
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Director of Endocrine Head & Neck Surgery
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Professor of Otolaryngology/Head & Neck Surgery
15
Stanford University School of Medicine
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Stanford, California
17 18
Sharon S. Raimer, MD
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Professor, Dermatology and Pediatrics
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Chair, Department of Dermatology
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University of Texas Medical Branch
22
Galveston, Texas
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1
TEMPORARY MEMBERS (Voting) (cont.)
2
Elaine Siegfried, MD
3
(Afternoon Session Only)
4
Professor, Pediatrics and Dermatology
5
Director, Division of Pediatric Dermatology
6
Saint Louis University
7
St. Louis, Missouri
8 9
Maral Kibarian Skelsey, MD
10
(Morning Session Only)
11
Director, Dermatology and Clinical Assistant
12
Professor
13
Department of Dermatology
14
Georgetown University
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Washington, District of Columbia
16 17
Kenneth E. Towbin, MD
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(Afternoon Session Only)
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Chief, Clinical Child & Adolescent Psychiatry
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Emotion and Development Branch
21
National Institute of Mental Health, NIH
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Bethesda, Maryland
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TEMPORARY MEMBERS (Voting) (cont.)
2
Carmen Myrie Williams, MD
3
Clinical Professor of Dermatology and Pathology
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George Washington University Medical Center
5
Dermatopathologist
6
Bethesda Dermpathology Lab
7
Bethesda, Maryland
8 9
FDA PARTICIPANTS (Non-Voting)
10
Julie Beitz, MD
11
(Afternoon Session Only)
12
Director
13
Office of Drug Evaluation III (ODE III)
14
Office of New Drugs (OND), CDER, FDA
15 16
Amy Egan, MD, MPH
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(Morning Session Only)
18
Deputy Director
19
ODE III, OND, CDER, FDA
20 21 22
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FDA PARTICIPANTS (Non-Voting) (cont.)
2
Jill Lindstrom, MD
3
(Afternoon Session Only)
4
Clinical Team Leader
5
DDDP, ODE III, OND, CDER, FDA
6 7
Kendall A. Marcus, MD
8
Director
9
Division of Dermatology and Dental Products (DDDP)
10
ODE III, OND, CDER, FDA
11 12
David Kettl, MD
13
(Morning Session Only)
14
Acting Deputy Director
15
DDDP, ODE III, OND, CDER, FDA
16 17
Michelle Roth-Cline, MD, PhD
18
(Afternoon Session Only)
19
Pediatric Ethicist
20
Office of Pediatric Therapeutics (OPT)
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Office of the Commissioner (OC), FDA
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C O N T E N T S
1 2
AGENDA ITEM
3
Call to Order
4 5 6 7 8 9
PAGE
Lynn Drake, MD Conflict of Interest Statement Jennifer Shepherd, RPh
Kendall Marcus, MD
11
Responsive to Topical Therapy Overview and
12
Available Therapy Jill Lindstrom, MD, FAAD
14
Dupilumab as an Example of a Product in
15
Development for Atopic Dermatitis
16
Inadequately Responsive to Topical Therapy
18
28
FDA Presentations Atopic Dermatitis Inadequately
17
23
FDA Introductory Remarks
10
13
16
Jane Liedtka, MD, FAAD Clarifying Questions
19 20 21 22
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48 53
15
C O N T E N T S (continued)
1 2
AGENDA ITEM
PAGE
3
Industry Presentations
4
Pediatric Development of Systemic
5
Products for the Treatment of Atopic
6
Dermatitis with Inadequate Response to
7
Topical Prescription Therapy
8
Rene van der Merwe, MBChB, MSc, FFPM
70
9
Athos Gianella-Borradori, MD
81
10
Clarifying Questions
11
FDA Presentations – Ethicist
12
Ethical Considerations in the Development of
13
Products for Use in Pediatric Patients with
14
Atopic Dermatitis
15
Michelle Roth-Cline, MD, PhD
94
129
16
Clarifying Questions
139
17
Open Public Hearing
147
18
Questions to the Committee and Discussion
174
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Adjournment
238
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P R O C E E D I N G S
1
(1:06 p.m.)
2 3
Call to Order
4
Introduction of Committee DR. DRAKE:
5
Good afternoon.
I'm going to
6
reconvene the advisory board.
7
housekeeping as usual, I'd like to remind everyone
8
to please silence your cellphones, your
9
smartphones, and any other devices if you've not
10
already done so. I want to identify the FDA press contact,
11 12
Andrea Fischer.
13
Andrea.
14
First of all,
She's back there in the back.
Hi,
Thanks. Keep in mind, sometimes the press wants to
15
talk to you or wants to talk to us, and it's
16
probably better to always make sure that Andrea is
17
involved in that loop at some level because she
18
should handle most of the press calls.
19
we keep it organized.
That way,
20
The next thing I'd like to do is I would
21
like to have everybody introduce themselves, and
22
I'll start.
I'm Lynn Drake, and I'm a lecturer at
A Matter of Record (301) 890-4188
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1
Harvard Medical School.
2
Massachusetts General Hospital.
3
I'm a dermatologist at the
With that, I'd like to go around the room
4
and have everybody introduce themselves.
5
give me your name and your affiliation or any
6
important information we should know about you that
7
will help us this afternoon.
8
DR. CORCORAN:
9
Gavin Corcoran.
Good afternoon.
Please
My name is
I'm the chief medical officer at
10
Actavis, and I am the industry representative on
11
the committee.
12
DR. TOWBIN:
I'm Kenneth Towbin.
I'm a
13
child and adolescent psychiatrist at the intramural
14
program of the National Institute of Mental Health
15
and the current chair of the Pediatric Advisory
16
Committee.
17
DR. KOPELMAN:
Hello.
I'm Loretta Kopelman.
18
My degree is in philosophy, and my career, I've
19
worked in bioethics.
20
the Brody School of Medicine, and I am currently
21
teaching at Georgetown.
22
DR. GREEN:
I am professor emeritus from
Hi, I'm Brian Green.
A Matter of Record (301) 890-4188
I'm a
18
1
pediatric dermatologist in the army stationed at
2
Walter Reed.
3
DR. HORII:
I'm Kimberly Horii.
I'm a
4
pediatric dermatologist from Children's Mercy
5
Hospital in Kansas City.
6
DR. COHEN:
I'm Bernard Cohen, professor of
7
pediatrics and dermatology at the Johns Hopkins
8
Children Center.
9
DR. KATZ:
I'm Ken Katz.
I'm a
10
dermatologist at Kaiser Permanente in Pleasanton,
11
California.
12
DR. BERGFELD:
I'm Wilma Bergfeld.
I'm a
13
dermatologist and dermatopathologist from the
14
Cleveland Clinic, Cleveland, Ohio.
15
DR. RAIMER:
Sharon Raimer.
I'm a professor
16
of dermatology and pediatrics at the University of
17
Texas Medical Branch in Galveston, Texas.
18
MS. BOYCE:
Danielle Boyce.
I'm a patient
19
representative, and I also work at Johns Hopkins,
20
completely unrelated, in the pulmonary division.
21 22
DR. MALONEY:
Hi, I'm Mary Maloney.
I'm a
dermatologist at the University of Massachusetts in
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1 2
Western Mass. LCDR SHEPHERD:
Jennifer Shepherd,
3
designated federal officer.
4
DR. MYRIE-WILLIAMS:
5 6 7 8 9
DR. BILKER:
DR. BRITTAIN:
DR. GASPARI:
15 16 17
I'm a
Erica Brittain.
I'm a
statistician at National Institute of Allergy and
11
14
Warren Bilker.
biostatistician at the University of Pennsylvania.
Infectious Diseases.
13
Tony Gaspari, dermatology,
University of Maryland, Baltimore. DR. DiGIOVANNA:
John DiGiovanna,
dermatologist, National Cancer Institute, NIH. DR. SIEGFRIED:
I'm Elaine Siegfried, a
pediatric dermatologist at St. Louis University. DR. CANTATORE-FRANCES:
Julie Cantatore-
18
Francis.
19
Connecticut in private practice in New Haven
20
Hospital.
21 22
I'm a
dermatologist and dermatopathologist here in town.
10
12
Carmen Williams.
I'm a pediatric dermatologist in
DR. ROTH-CLINE:
I'm Michelle Roth-Cline.
I'm a pediatric ethicist in the Office of Pediatric
A Matter of Record (301) 890-4188
20
1
Therapeutics here at the agency. DR. LINDSTROM:
2
I'm Jill Lindstrom, a
3
dermatologist and lead medical officer in the
4
Division of Dermatology and Dental Products here at
5
FDA. DR. MARCUS:
6
Good afternoon.
I'm Kendall
7
Marcus, director of the Division of Dermatology and
8
Dental Products. DR. BEITZ:
9 10
I'm Julie Beitz, director of the
Office Drug Evaluation III. DR. DRAKE:
11
Thank you so much.
First of
12
all, I want to start off by thanking all of you for
13
being here today.
14
morning session, and some of you were involved in
15
that.
16
This is a real treat.
We had a
But the panel this morning and this
17
afternoon are both exemplary in terms of the
18
membership.
19
and the diversity and the expertise sitting around
20
this table.
21
you came particularly for this afternoon because
22
some of the questions are -- I mean, they're really
I mean, I can't believe the quality,
So I'm very appreciative that each of
A Matter of Record (301) 890-4188
21
1
important questions.
Thank you for taking time out
2
of your lives, and your practices and your offices
3
to come. I'd like to compliment the FDA.
4
You know,
5
just putting this panel together.
I've served on
6
lots of panels, but the two today have just been
7
out of sight in terms of really just dynamite
8
people.
Thank you so much for doing that. I think it'll make this session really go
9 10
well.
Hopefully, we'll get to some of the answers,
11
to some of the questions and some guidance that you
12
hoped this committee will help you with.
13
thank you all very much.
So I
14
Having said that, what I want to do is say,
15
for topics such as those being discussed at today's
16
meeting, there are often a variety of opinions,
17
some of which are quite strongly held.
18
image that, can you?
19
You can't
Anyway, our goal is today's meeting will be
20
a fair and open forum for discussion of these
21
issues and that individuals can express their views
22
without interruption.
Thus, as a gentle reminder,
A Matter of Record (301) 890-4188
22
1
individuals will be allowed to speak into the
2
record only if recognized by the chair, and we look
3
forward to a productive meeting. By the way, when I say "recognized by the
4 5
chair," if you have something to say when it's the
6
appropriate time, just raise your hand and nod, and
7
let Lieutenant Commander Shepherd here catch your
8
eye or me, or one of us will catch your eye, and
9
we'll list you in the order of which we spot you.
10
That's the order on which I'll call upon you.
11
right?
12
All
So we try to keep it fair. If you don't speak up, you might as well
13
just go ahead and raise your hand and say something
14
because I'm going to call on you sooner or later if
15
you don't speak up.
16
because you're all important to this process.
You're all here for a reason,
17
So in the spirit of the Federal Advisory
18
Committee Act and the government in the Sunshine
19
Act, we ask that the advisory committee members
20
take care that their conversations about the topic
21
at hand take place in the open forum of the
22
meeting.
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23
1
We're aware that members of the media are
2
anxious to speak with the FDA about these
3
proceedings.
4
discussing the details of this meeting with the
5
media until its conclusion.
6
reminded to please refrain from discussing this
7
meeting topic during breaks or lunch.
8 9
However, FDA will refrain from
Commander Jennifer Shepherd -- by the way who has been doing a superb job.
11
good team.
12
Interest Statement please.
14
Thank you.
Now, what I'm going to do is ask Lieutenant
10
13
Also, the committee is
I mean we're a pretty
I'll ask her to read the Conflict of
Conflict of Interest Statement LCDR SHEPHERD:
Thank you, Dr. Drake.
The
15
Food and Drug Administration is convening today's
16
meeting of the Dermatologic and Ophthalmic Drugs
17
Advisory Committee under the authority of the
18
Federal Advisory Committee Act of 1972.
19
With the exception of the industry
20
representative, all members and temporary voting
21
members of the committee are special government
22
employees or regular federal employees from other
A Matter of Record (301) 890-4188
24
1
agencies and are subject to federal conflict of
2
interest laws and regulations.
3
The following information on the status of
4
this committee's compliance with federal ethics and
5
conflict of interest laws, covered by but not
6
limited to those found at 18 U.S.C. Section 208, is
7
being provided to participants in today's meeting
8
and to the public.
9
and temporary voting members of this committee are
FDA has determined that members
10
in compliance with federal ethics and conflict of
11
interest laws.
12
Under 18 U.S.C. Section 208, Congress has
13
authorized the FDA to grant waivers to special
14
government employees and regular federal employees
15
who have potential financial conflicts when it is
16
determined that the agency's need for a particular
17
individual's services outweighs his or her
18
potential financial conflict of interest.
19
Related to the discussions of today's
20
meeting, members and temporary voting members of
21
this committee have been screened for potential
22
financial conflicts of interest of their own as
A Matter of Record (301) 890-4188
25
1
well as those imputed to them, including those of
2
their spouses or minor children, and, for purposes
3
of 18 U.S.C. Section 208, their employers.
4
These interests may include investments,
5
consulting, expert witness testimony, contracts,
6
grants, CRADAs, teaching, speaking, writing,
7
patents and royalties, and primary employment.
8
This afternoon, the committee will discuss
9
pediatric development of systemic products for the
10
treatment of atopic dermatitis with inadequate
11
response to topical prescription therapy.
12
a particular matters meeting during which general
13
issues will be discussed.
14
This is
Based on the agenda for today's meeting and
15
all financial interests reported by the committee
16
members and temporary voting members, no conflict
17
of interest waivers have been issued in connection
18
with this meeting.
19
To ensure transparency, we encourage all
20
standing members and temporary voting members to
21
disclose any public statements that they have made
22
concerning the topic at issue.
A Matter of Record (301) 890-4188
26
With respect to FDA's invited industry
1 2
representatives, we would like to disclose that
3
Dr. Gavin Corcoran is participating in this meeting
4
as a nonvoting industry representative acting on
5
behalf of regulated industry.
6
at this meeting is to represent industry in general
7
and not any particular company.
8
employed by Actavis.
Dr. Corcoran's role
Dr. Corcoran is
We would like to remind members and
9 10
temporary voting members that if the discussions
11
involve any other products or firms not already on
12
the agenda for which an FDA participant has a
13
personal or imputed financial interest, the
14
participants need to exclude themselves from such
15
involvement, and their exclusion will be noted for
16
the record. FDA encourages all other participants to
17 18
advise the committee of any financial relationships
19
that they may have with the firms that could be
20
affected by the committee's discussions.
21
you.
22
DR. DRAKE:
Thank you, Jennifer.
A Matter of Record (301) 890-4188
Thank
So the
27
1
order of business this afternoon -- you have the
2
agenda in your books.
3
presentations -- we'll begin in just a minute with
4
Dr. Marcus.
5
We will have
There will be an FDA presentation, and then
6
clarifying questions.
And by clarifying questions,
7
we want questions you might want to ask.
8
will have a quick break.
9
presentations about the conundrums, and questions,
Then we
We'll have industry
10
and concerns they have in order for us to give good
11
advice, and then we'll have clarifying questions.
12
Then we'll have time for open public
13
hearing.
14
the open public hearing, which by the way, I view
15
as equally important because sometimes what comes
16
forward from the public during the public hearing
17
is tremendously helpful to the committee.
18 19 20
This afternoon, we have, I think five for
Then there'll be a charge to the committee, and then we'll do the questions and discussions. There's not actually a vote today in terms
21
of voting on a product, but more on how should we
22
proceed with some of these dicey questions, some of
A Matter of Record (301) 890-4188
28
1
these dicey questions, some of these little spicy
2
questions.
3 4 5 6
With that, I'd like to ask Dr. Marcus to please come and do her introductory statement. FDA Introductory Remarks – Kendall Marcus DR. MARCUS:
Good afternoon.
I think I'm a
7
little more awake now this afternoon than I was
8
this morning, so I may use my slides this time and
9
properly identify the order of the speakers.
10
First, I would like to echo Lynn's comments
11
about the advisory committee and acknowledge the
12
extraordinary efforts of my colleagues in
13
recruiting qualified members of the advisory
14
committee.
15
I think their efforts have really paid off
16
well, and my hat's off to Dave Kettl for recruiting
17
for this morning's advisory committee and to Jill
18
Lindstrom and Jane Liedtka for identifying
19
committee members for this afternoon.
20
Today, we will be discussing pediatric
21
product development for refractory atopic
22
dermatitis.
I'd like to provide you with some
A Matter of Record (301) 890-4188
29
1
historical perspectives on pediatric product
2
development across various indications, and then
3
provide you also with some very high-level
4
questions for consideration as you hear the
5
presentations today prior to your discussion.
6
I'll be talking about products under
7
development for psoriasis as well as two products
8
developed for the treatment of hepatitis C and one
9
developed for pancreatic insufficiency due to
10 11
cystic fibrosis. The Division of Dermatology and Dental
12
Products have approved a number of both biologic
13
and drug products for treatment of patients with
14
moderate to severe psoriasis in adult populations.
15
They first considered approval of a product for
16
psoriasis for pediatric population in 2008.
17
A pediatric study was conducted and data
18
submitted to the FDA in a marketing application for
19
etanercept for the indication of psoriasis.
20
application was taken to public advisory committee
21
for consideration due to malignancy concerns.
22
concluded that evidence available at that time
A Matter of Record (301) 890-4188
The
They
30
1
neither confirmed nor refuted causal association
2
for malignancy.
3
The sponsor subsequently withdrew their
4
application for the pediatric population, and the
5
FDA subsequently released the sponsor from any
6
pediatric study requirements.
7
decision, the FDA took the following actions
8
regarding pediatric study of the following products
9
for psoriasis.
10
Subsequent to that
Just to provide you with some context,
11
regulations require that the sponsors conduct
12
trials in pediatric populations for products that
13
receive approval for adult indications.
14
requirement can be waived if it's considered
15
infeasible to conduct a study in a pediatric
16
population or if there are other concerns that
17
would preclude study of the product for pediatrics.
18
That
All of the following products for the
19
indication of psoriasis subsequently were either
20
released from their pediatric study requirements,
21
had their study requirements waived, or had them
22
deferred until additional data post-marketing could
A Matter of Record (301) 890-4188
31
1
be collected in adults to further inform the safety
2
profile.
3
Interferon and ribavirin, until recently,
4
was the standard of care for hepatitis C.
5
two products, when given concomitantly, have a
6
quite serious adverse effect profile, which can
7
include very serious or life-threatening events.
8
Despite this, a pediatric study was conducted that
9
enrolled 114 subjects.
10
These
Safety issues unique to a pediatric
11
population were identified in this study, and it
12
was observed that at two years post treatment
13
follow-up, delays in weight and height gains that
14
were observed during the clinical trials still
15
existed for a subset of patients.
16
Sixteen percent of subjects remained at
17
least 15 percentiles below their baseline weight
18
curve and 11 percent remained at least
19
15 percentiles or more below their baseline height.
20
Despite these observations, the combination of
21
interferon and ribavirin was approved for use in
22
pediatric populations, and a warning was added to
A Matter of Record (301) 890-4188
32
1
product labeling.
2
In another example, liprotamase for
3
pancreatic insufficiency in pediatric patients with
4
cystic fibrosis was evaluated.
5
enrolled 214 subjects, and similarly, losses in
6
height, weight, and BMI z-scores appeared to occur
7
during the clinical trial.
8
both 7 to 11-year-old cohorts, and to a lesser
9
extent the 12 to 16 year-old age cohort.
10
A pediatric study
This was observed in
This study was submitted in a formal
11
marketing application, and this was also taken to
12
an advisory committee.
13
evaluate long-term outcomes, but the long-term
14
outcomes of administration of this product to
15
pediatric subjects was not clear.
16
subsequently, the marketing application was not
17
approved.
18
The sponsor did attempt to
And
I wanted to provide you with those examples
19
just to provide you some context for today's
20
discussion.
21
emphasize that none of the actions -- I would
22
encourage you not to see any of these actions as
I just want to take a moment and
A Matter of Record (301) 890-4188
33
1
right or wrong.
2
provide you with context and perspective for
3
today's discussion.
4
I'm simply presenting these to
These are some of the questions that I hope
5
you will consider as you hear the subsequent
6
presentations.
7 8 9
Is there an unmet medical need for pediatric populations with refractory atopic dermatitis? How much data should be collected in adults
10
prior to pediatric evaluation of products for
11
refractory atopic dermatitis if you think there is
12
an unmet medical need?
13
How much uncertainty would you tolerate when
14
considering the timing of the initiation of such
15
studies?
16
Does the potential for novel safety issues
17
in pediatric populations change the risk-benefit in
18
your opinion?
19 20 21 22
Do we need to know if drugs have long-term effects in pediatric populations? Finally, I would like you to think about and describe appropriate pediatric populations that
A Matter of Record (301) 890-4188
34
1
might be enrolled in clinical trials for refractory
2
atopic dermatitis.
3
With that, I would like to turn the podium
4
over to my colleague, Dr. Jill Lindstrom for her
5
presentation.
6 7
FDA Presentation – Jill Lindstrom DR. LINDSTROM:
Good afternoon.
Today, I'm
8
going to provide you with a high-level overview of
9
atopic dermatitis, focusing on the upper end of
10
disease severity.
11
level, the treatment of atopic dermatitis focusing
12
on available therapies for atopic dermatitis that
13
is inadequately responsive to topical therapy.
14
then I'll turn the podium over to my colleague,
15
Dr. Jane Liedtka, who will discuss from the
16
literature, dupilumab as an example of a product in
17
development for this indication.
18
I'll also discuss, at a high
Atopic dermatitis is a chronic,
19
inflammatory, pruritic skin disease that affects
20
primarily children, but it also affects adults.
21
Prevalence estimates vary and range as high as
22
30 percent in children and 10 percent in adults.
A Matter of Record (301) 890-4188
And
35
1
Onset is typically in childhood with almost
2
half of patients experiencing disease onset by
3
6 months of age, over half by 1 year of age, and
4
85 percent by 5 years of age.
5
disease severity.
6
in the United States, approximately 18 percent of
7
patients self-reported their disease as severe.
8 9
There is a range of
In one large epidemiologic study
Pruritis is the cardinal symptom of atopic dermatitis.
It is universally present, and it is a
10
required element for the diagnosis.
11
cutaneous exam, one sees a dermatitic picture with
12
papules, vesicles, plaques, and erosions, secondary
13
characteristics of scales and crust, perhaps
14
lichenification or hypopigmentation.
15
Clinically, on
Distribution can vary by age with the face,
16
neck, and extensor surfaces typically involved in
17
infants and young children, the flexors commonly
18
involved at any age.
19
the groin, it can otherwise be widespread.
20
lesions of atopic dermatitis proper occur on a
21
generalized background of xerosis.
22
And while the disease spares The
I'm indebted to my colleagues, Drs. Amy
A Matter of Record (301) 890-4188
36
1
Paller and Larry Eichenfield for the following
2
clinical images.
3
widespread involvement with papules coalescent into
4
plaques on the chest, abdomen, upper extremities
5
and lower extremities.
6
periareolar involvement, which is a hallmark of the
7
disease.
8 9
Here, you see an infant with
Note the prominent
This is another infant again with widespread involvement.
You can see involvement on the upper
10
extremities, chest and neck.
But what's most
11
notable in this photograph is the facial
12
involvement with erythematous papules, plaques,
13
erosions, crusted lesions, hemorrhagic crusts, and
14
serous crusts, and also the obvious distress of the
15
patient.
16
Here is an older child, a toddler.
Due to
17
the darker pigmentation, it may be a little harder
18
from where you are to appreciate the widespread
19
involvement.
20
plaques involving the face, neck, chest, abdomen,
21
flank, upper extremities and lower extremities.
22
You can appreciate scale and large areas of
There are erythematous papules and
A Matter of Record (301) 890-4188
37
1
crusting, and also the patient's attempts to
2
scratch despite their caretaker's attempts to
3
prevent this.
4
Here is an older child again with widespread
5
involvement, papules coalescent into plaques,
6
erosions and crusts affecting the face, neck,
7
chest, abdomen, and arms.
8
and erosions suggesting excoriation around the neck
9
and on the antecubitum.
Note the linear crusts
And here is the same
10
patient seen from the back again with widespread
11
involvement, almost no areas without disease
12
involvement.
13
My final picture is a child with a more
14
acute presentation, again widespread disease,
15
almost no clear skin visible on this photograph,
16
erythematous papules, erosions, weeping, crusting,
17
hemorrhagic crusting, scale.
18
When I look at this child and the picture of
19
the previous child, I'm struck as I consider what
20
might be the impact of their disease on their
21
school performance, on their social interactions,
22
their interactions with peers, their ability to
A Matter of Record (301) 890-4188
38
1
participate in sports or in social activities such
2
as swimming.
3
When you consider these images, which
4
admittedly are of children with disease at the
5
upper end of the severity, it's not surprising that
6
when evaluated, it's been identified that atopic
7
dermatitis impairs children's quality of life.
8
degree of impairment is associated with disease
9
severity.
10
The
Using the children's life quality index
11
instrument and looking at children with atopic
12
dermatitis and other diseases, it's been found that
13
the health-related quality of life impairment in
14
generalized atopic dermatitis exceeds that seen in
15
asthma, epilepsy, and dermatitis; is comparable to
16
that in renal disease; and equals or exceeds that
17
seen in psoriasis.
18
But it's not just the quality of life of the
19
patient that is impaired.
Quality of life of the
20
families are also impaired.
21
the patient, the degree of impairment for the
22
family correlates with disease severity.
And as it's seen with
A Matter of Record (301) 890-4188
39
1
When looking at family quality of life,
2
using a survey instrument by Stein and Reisman,
3
it's been found that the impairment scores are
4
comparable in mild atopic dermatitis or exceed in
5
moderate or severe atopic dermatitis, those
6
obtained from families of children with diabetes.
7
When looking at the individual domains of
8
this instrument, the investigators found that
9
families reported that the daily time used for
10
treatment range from 1 and a half to 3 hours.
The
11
daily hours of sleep lost for both the children and
12
parents range from 1 to 2 hours.
13
A different survey instrument, the
14
Dermatitis Family Impact Questionnaire, found that
15
a majority of families, particularly caregivers in
16
this instance, reported burden from the care,
17
feelings of guilt, exhaustion, and frustration;
18
reported that their family life was not normal
19
anymore.
20
affected children and their unaffected siblings.
21
The affected children had difficulties in school
22
and reported behavioral disturbances during disease
There was sleep impairment for their
A Matter of Record (301) 890-4188
40
1 2
flares. Atopic dermatitis has been associated with
3
sleep disruption in children affected, and it's
4
been reported in up to 85 percent of these children
5
during disease flares.
6
manifested by delayed onset of sleep, increased
7
nighttime wakening, and delayed onset of REM.
8 9
The sleep disruption is
The degree of sleep disruption is correlated with the severity of their disease and results not
10
surprisingly in behavioral deficits and decreased
11
neurocognitive function.
12
comorbidities have been associated in children with
13
atopic dermatitis such as depression, anxiety,
14
conduct disorder, and learning delay.
15
A number of psychiatric
Asthma, allergic rhinitis, and food
16
allergies have been long known to be associated
17
with atopic dermatitis.
18
increased prevalence and an increased severity in
19
patients with atopic dermatitis, and these three
20
conditions, asthma, rhinitis and allergic rhinitis,
21
the severity of these three conditions is
22
correlated with the severity of the atopic
They occur with an
A Matter of Record (301) 890-4188
41
1
dermatitis. Both cutaneous and extracutaneous infections
2 3
occurred in increased incidence in patients with
4
atopic dermatitis.
5
with atopic dermatitis are colonized with
6
Staph aureus, and the density of colonization is
7
correlated with disease severity. In light of the cutaneous disruption in the
8 9
Up to 90 percent of patients
disease, it's not surprising then that we see both
10
superficial cutaneous infections such as impetigo
11
and deeper cutaneous infections such as cellulitis
12
in these patients.
13
of viral infections such as herpes simplex,
14
molluscum, and warts.
15
infections -- HSV and vaccinia -- can present in a
16
severe generalized and potentially fatal form.
There's an increased incidence
And some viral
Obesity is correlated with increased
17 18
severity of atopic dermatitis in both children and
19
adults.
20
children with moderate to severe atopic dermatitis,
21
they not only have increased body mass indexes and
22
increased waist circumference, but they also have
It's been recently reported that for
A Matter of Record (301) 890-4188
42
1
higher systolic and diastolic blood pressure even
2
after control for their BMI, waist circumference,
3
and prior prednisone and cyclosporine use.
4
I'm going to change gears now and briefly
5
discuss treatment.
6
of Dermatology published treatment guidelines for
7
atopic dermatitis.
8
discusses topical therapy and outlines the
9
following approach.
10
In 2014, the American Academy
Section 2 of these guidelines
Non-pharmacologic measures are foundational
11
for the treatment of atopic dermatitis.
They
12
include things such as moisturizers, emollients,
13
bathing practices, and for acute flares wet-wrap
14
therapy.
15
some cases, particularly mild cases, sometimes be
16
sufficient to treat the disease.
17
step would be topical corticosteroids.
These non-pharmacologic measures can, in
If not, the next
18
A variety of topical corticosteroids are
19
approved for the indication of atopic dermatitis
20
from the low potency hydrocortisone available over-
21
the-counter to higher potency products available by
22
prescription.
Some products contain age
A Matter of Record (301) 890-4188
43
1 2
restrictions in their labeling. Finally, topical calcineurin inhibitors are
3
approved as second-line therapy for treatment of
4
atopic dermatitis, tacrolimus for moderate to
5
severe disease, and pimecrolimus for mild to
6
moderate disease.
7
will be adequate for many patients with atopic
8
dermatitis but not for all patients.
9
In combination, these measures
Section 3 of the aforementioned guidelines
10
address systemic and phototherapy of atopic
11
dermatitis.
12
of the guidelines recommends systemic therapy for
13
adult and pediatric patients in whom optimized
14
topical regimens do not adequately control the
15
signs and symptoms of the disease or for patients
16
whose medical, physical, or psychological states
17
are greatly affected by their disease.
18
Regarding systemic therapy, Section 3
The guidelines discuss these five agents, or
19
in the case of systemic corticosteroids, group of
20
agents, and I will discuss them sequentially and
21
briefly.
22
discussing these five agents the AAD guidelines
I'll use as my sources of information in
A Matter of Record (301) 890-4188
44
1
referenced on this slide as well as approved
2
product labeling.
3
First, systemic corticosteroids.
4
11 systemic corticosteroids listed on this slide
5
that are approved for the treatment of atopic
6
dermatitis, specifically for the control of severe
7
or incapacitating disease intractable to adequate
8
trials of conventional treatment.
9
There are
However, there is no clinical trial data for
10
atopic dermatitis in the labeling of these
11
corticosteroids.
12
depending on the product, information about
13
pediatric dosing.
14
There's incomplete or absent,
There's a note that vaccine efficacy may be
15
impaired during the use of these corticosteroids,
16
and approved labeling includes warnings for growth
17
impairment in children, HPA axis suppression,
18
increased risk of infection, and other adverse
19
reactions.
20
Of note, the AAD guidelines state, "Systemic
21
steroids should generally be avoided in adults and
22
children with atopic dermatitis because the
A Matter of Record (301) 890-4188
45
1
potential short- and long-term adverse effects
2
largely outweigh the benefits."
3
The second systemic agent I'll discuss is
4
cyclosporine.
The AAD guidelines note that it may
5
provide a reduction in the signs and symptoms of
6
atopic dermatitis.
7
the FDA for this indication.
8
limited pediatric dose information, a note that
9
vaccine efficacy may be decreased.
However, it's not approved by Labeling includes
And labeling
10
includes a boxed warning for malignancies,
11
infections, hypertension, and nephrotoxicity.
12
The third agent is azathioprine.
13
guidelines note that in controlled trials, 26 to
14
37 percent of subjects have been reported to
15
experience improvement in their disease in their
16
atopic dermatitis.
17
The AAD
However, azathioprine is not FDA-approved
18
for this indication.
Labeling does not contain
19
pediatric-specific dose information, but it does
20
contain a boxed warning regarding malignancies
21
including hepatosplenic T-cell lymphoma, which is
22
aggressive in children.
Additionally, labeling
A Matter of Record (301) 890-4188
46
1
contains warnings for bone marrow suppression,
2
serious infections, and a notation that the product
3
is both a mutagen and a teratogen.
4
The fourth agent I'll discuss is
5
methotrexate.
6
treatment effect for this agent is unclear.
7
not FDA-approved for the treatment of atopic
8
dermatitis.
9
pediatric-specific dose information, notes that
10
vaccine efficacy may be impaired and contains a
11
boxed warning with information about multiple
12
toxicities, some of which may be fatal.
13
The AAD guidelines report that the It is
Labeling again contains limited
The last agent that I'll discuss is
14
mycophenolate mofetil, which the AAD guidelines
15
note should be considered an alternative therapy
16
because the treatment effect is reported to be
17
variable.
18
of atopic dermatitis.
19
It is not FDA-approved for the treatment
In labeling, there's limited
20
pediatric-specific dose information, a notation
21
that vaccine efficacy may be impaired, and labeling
22
contains a boxed warning for malignancy, serious
A Matter of Record (301) 890-4188
47
1
infection, pregnancy loss, and congenital
2
malformations, as well as warnings for bone marrow
3
suppression and serious GI and cutaneous adverse
4
reactions. In summary, I've discussed that atopic
5 6
dermatitis, particularly at the upper end of
7
disease severity, can be a serious disease with
8
multiple comorbidities and significant impact on
9
patients and families' quality of life. I've discussed that published practice
10 11
guidelines recommend the use of systemic treatment
12
for patients in whom optimized topical therapy is
13
unsuccessful or whose disease significantly impacts
14
their life.
15
therapies, which include systemic corticosteroids
16
and systemic immunosuppressant drugs used off-
17
label.
And I've discussed available
18
Now, I'll turn over the podium to my
19
colleague, Dr. Jane Liedtka, who will discuss, from
20
the literature, dupilumab as an example of a
21
product in development for atopic dermatitis
22
inadequately responsive to topical therapy.
A Matter of Record (301) 890-4188
48
FDA Presentation – Jane Liedtka
1 2
DR. LIEDTKA:
Good afternoon.
My name is
3
Jane Liedtka, and I'm a dermatologist and a medical
4
officer for the Division of Dermatology and Dental
5
Products.
6
Dupilumab is a fully human monoclonal
7
antibody that blocks IL-4 and IL-13.
These
8
interleukins are key drivers of type 2 helper cell
9
T-cell mediated inflammation.
Atopic dermatitis
10
has been classified as a TH2 dominated disease.
11
Dupilumab has been studied in adults with asthma,
12
and atopic dermatitis.
13
In 2014, Beck et al reported studies on
14
dupilumab treatment in adults with moderate to
15
severe atopic dermatitis in the New England Journal
16
of Medicine.
17
double-blind, placebo-controlled trials of once
18
weekly dupilumab in moderate to severe atopic
19
dermatitis, not responsive to topical therapy, were
20
discussed.
21 22
In that article, four randomized,
The inclusion criteria for these four trials included that the subjects were 18 years of age and
A Matter of Record (301) 890-4188
49
1
older, that they had an Investigator's Global
2
Assessment Scale score of greater than or equal to
3
3, which was on a 5-grade scale; 3 was the
4
equivalent of moderate. In addition, patients needed to have an
5 6
Eczema Area and Severity Index Scale, which is also
7
known as the EASI, of greater than or equal to 12
8
to 16.
9
to be greater than or equal to 10 to 15 percent,
Their body surface area of involvement had
10
and they had to have a diagnosis of atopic
11
dermatitis for at least two to three years.
12
This slide gives a little bit more
13
information about these four trials.
14
trial, M4A, was conducted in the United States.
15
was a sequential dose escalation monotherapy trial
16
that lasted for 4 weeks, in which 6 subjects were
17
treated with placebo and 24 subjects were treated
18
with dupilumab, equally divided between doses of
19
75, 150, and 300 mg.
20
The first It
The second trial, M4B, was a similar 4-week
21
dose escalation monotherapy trial, which is a
22
multinational trial.
In this trial, there were
A Matter of Record (301) 890-4188
50
1
10 subjects treated with placebo and 27 subjects
2
treated with dupilumab about equally divided
3
between 150 milligram and 300 milligram doses. The third trial, C4, was conducted in
4 5
Europe.
This was also a 4-week trial but involved
6
treatment with dupilumab at the same time as the
7
subjects were treated with topical corticosteroids.
8
In this trial, there were 10 subjects in the
9
placebo plus topical coriticosteroid group and 21
10
subjects in the dupilumab group who were treated at
11
a dose of 300 milligrams in addition to their
12
topical steroids.
13
Finally, the last trial, M12, also a
14
European trial, was a 12-week monotherapy trial.
15
Fifty-four subjects were treated with placebo and
16
55 subjects were treated with dupilumab at a dose
17
of 300 milligrams.
18
This slide describes some clinical
19
characteristics of the subjects at baseline.
20
EASI score, which is, as I'd mentioned previously,
21
the Eczema Area and Severity Index score, which can
22
vary between zero and 70, varied in the subjects
A Matter of Record (301) 890-4188
The
51
1 2
treated in these trials from 23 to 31. The IGA score varied from 3.4 to 4.
The
3
body surface area of involvement varied from 39
4
percent to a high of 51 percent.
5
Numerical Rating Score, which is on a scale of zero
6
to 10, varied from 5 to 6.4
7
And the pruritis
This slide depicts the key efficacy
8
endpoints for the two 4-week monotherapy trials,
9
which were combined because they were similar in
10
study design.
11
dose of dupilumab, depicted in red, approximately
12
70 to 80 percent of subjects achieved an EASI 50,
13
which is a 50 percent reduction in the EASI score
14
over the 4-week trial.
15
As you can see, the 300-milligram
This slide depicts the weekly pruritis
16
Numerical Rating Scale score also for the 4-week
17
monotherapy trials combined.
18
that the 300-milligram dupilumab dose depicted in
19
red, the subjects achieved approximately 50 percent
20
decrease in the pruritis NRS versus an
21
approximately 10 percent decrease in the placebo
22
subjects.
You can see again
A Matter of Record (301) 890-4188
52
In the 4-week trial that combined dupilumab
1 2
therapy with topical corticosteroids, 100 percent
3
of subjects in the dupilumab group achieved an EASI
4
50, again a 50 percent reduction in the EASI score
5
versus 50 percent of subjects in the placebo group.
6
It was also notable that the dupilumab-treated
7
subjects decreased their topical corticosteroid use
8
by 50 percent over the course of the trial. Finally, for the study, M12, the 12-week
9 10
monotherapy trial, this slide depicts the EASI 50
11
reduction, which approached 80-90 percent in the
12
dupilumab group at a dose of 300 milligrams versus
13
between 20 and 30 percent for the placebo group.
14
At the same time, the pruritis Numerical
15
Rating Scale score in the 12-week trial again
16
showed the dupilumab 300-milligram group with about
17
a 50 percent decrease in the NRS versus an
18
approximately 10 percent decrease for the placebo
19
group.
20
With regard to safety, the adverse events,
21
lab abnormalities, and changes in EKGs and vital
22
signs were reported to be similar between the
A Matter of Record (301) 890-4188
53
1
placebo and the dupilumab groups.
2
adverse events reported more frequently by
3
dupilumab-treated subjects included
4
nasopharyngitis, headache, and injection site
5
reactions.
6
The most common
With regard to serious adverse events, in
7
the 12-week monotherapy study, the rate of serious
8
adverse events in the placebo group exceeded that
9
in the dupilumab group.
When you look at the
10
serious adverse events in all the studies combined,
11
there were 13 of these events in 9 out of 80
12
subjects who were treated with placebo versus 2
13
events in 2 out of 127 subjects treated with
14
dupilumab.
15
events was primarily due to skin infections in
16
atopic dermatitis flares.
17 18
Thank you.
Are there any questions about the dupilumab portions of the presentation? Clarifying Questions
19 20
The imbalance in the serious adverse
DR. BILKER:
I think it's on slide 48.
21
looks like the 75-milligram dose does the best?
22
that right?
A Matter of Record (301) 890-4188
It Is
54
1
DR. LIEDTKA:
There is not a dose response
2
depicted in this slide for the pruritis Numerical
3
Rating score.
4
largest decrease, but as you noted, the
5
75-milligram group also did well on this.
6
there was a good placebo response in these
7
patients.
8 9
The dupilumab 300-group did have the
DR. DRAKE:
Again,
May I remind the committee that
please raise your hands and address the questions
10
through your chair, so that I can call on everybody
11
in order, anybody who has questions.
12
DR. BERGFELD:
Dr. Bergfeld?
This is not a question of the
13
speaker specifically, but in looking through the
14
presentation on the clinical and reviewing the
15
therapies that have been reported, I found a
16
lack -- and there is no mention of antibiotic
17
therapy and no mention of antihistamine therapy.
18
Is that because that is not in the literature?
19
It's so commonly used.
20
DR. LINDSTROM:
The systemic therapies that
21
I discussed came from the AAD guidelines part 3.
22
While they do discuss antihistamines, they do not
A Matter of Record (301) 890-4188
55
1
discuss -- did not recommend them as a systemic
2
therapy.
3
context of infection.
4
framework provided by the guidelines for systemic
5
therapies intended to directly treat the atopic
6
dermatitis.
7
Antibiotics are discussed as in the
DR. BERGFELD:
I limited my comments to the
But if your endpoint is
8
pruritis and reduction of pruritis -- I'm sorry.
9
I'd like the pediatric dermatologist to answer.
10 11 12
DR. DRAKE:
Wait.
One of the questions
is -- so your follow up question is? DR. BERGFELD:
One of the endpoints in all
13
the studies is reduction of pruritis, and
14
antihistamines are specifically addressing that as
15
well as reducing infection.
16
pediatric derms can respond.
17 18 19
DR. DRAKE:
So maybe one of the
Dr. Cohen, I think you had
a -- and then Dr. Siegfried. DR. COHEN:
Tony Cohen.
Briefly.
But in
20
the management guidelines review in the Children
21
Medical Academy of Dermatology, there are some
22
discussion of antihistamines, and basically the
A Matter of Record (301) 890-4188
56
1
data doesn't really support that it's of particular
2
value in reducing -- in management of children with
3
chronic atopic dermatitis. I mean I think from a practical standpoint,
4 5
it made sense not to include it in the review
6
today.
7
discussion -- there are some of us who occasionally
8
will use suppressive oral antibiotics.
9
there's very little data to show that that's of
And you agreed.
Also the
10
particular value.
11
not to include it in the review.
12 13 14
And again, I think a good reason
DR. DRAKE: Dr. Siegfried?
But again,
I'll come back to you.
Did you have a comment?
DR. SIEGFRIED:
I agree.
It's a
15
misconception, and it speaks to the little data
16
that we have for treating this disease.
17
popular to use antihistamines, sedating and
18
non-sedating as well as antibiotics, antibiotics
19
are recently selected in the Choosing Wisely
20
campaign as something that really shouldn't be
21
done, especially long term and for people who have
22
atopic dermatitis.
A Matter of Record (301) 890-4188
While it's
57
Sedating antihistamines are soporific but
1 2
non-sedating antihistamines have been shown in many
3
studies to not be effective for atopic dermatitis
4
itch.
5
DR. DRAKE:
Dr. Bergfeld again?
6
DR. BERGFELD:
Yes.
I am not a practicing
7
pediatric dermatologist.
I'm a general
8
dermatologist.
9
that -- and it's, I think, a pediatric opinion that
It is my opinion, however,
10
if you give antihistamines and reduce the rhinitis
11
or other drugs for asthma that you can reduce some
12
of the skin reaction also.
13
skin, you reduce the severity of the asthma and
14
other allergic systemic findings.
15
Is that not true?
16
DR. SIEGFRIED:
17
DR. COHEN:
And by controlling the
We only wish.
There's really no data to
18
support that.
19
in the children with atopic dermatitis.
20
many of us, we use it for the soporific effect to
21
which most children accommodate.
22
There is very little data to support And for
So a general rule, I think we try to steer
A Matter of Record (301) 890-4188
58
1
clear if we can, and you use it out of desperation.
2
But again, if you look at the data, there's just
3
very little data there that antihistamines have a
4
direct beneficial effect on the management of acute
5
or a chronic atopic dermatitis.
6
DR. DRAKE:
Dr. Siegfried?
7
DR. SIEGFRIED:
And there is emerging data
8
that use of sedating antihistamines actually impair
9
normal sleep; they're negative for normal sleep
10
hygiene, so their habit-forming and long-term use
11
needs more study for sure.
12
DR. DRAKE:
13
Other questions or clarifying points on this
Excellent question.
14
FDA presentation?
Nicely done, Jill.
15
you did a good job.
16
think it does point out there are a lot of holes
17
out there in the whole world of guidelines and
18
evidence-based medicine, isn't there?
19
beginning to --
That was very nicely done.
20
Dr. Katz, you have a question?
21
DR. KATZ:
22
And guys,
Yes.
I
And so we're
I have a question for FDA.
Given the unmet -- or the severity of the disease
A Matter of Record (301) 890-4188
59
1
and the lack of products with approved labeling
2
specific for atopic dermatitis, has the agency
3
thought about using powers under the Best
4
Pharmaceuticals for Children Act to specifically
5
address that unmet need with the existing products
6
that we know are used, which are mentioned in the
7
AAD guidelines but for which we don't have adequate
8
safety or effectiveness data?
9
DR. LINDSTROM:
Dr. Katz, that is an
10
excellent question.
11
we have convened this committee today.
12
forward to you and your fellow committee members
13
providing us further input when we get to the time
14
of discussion.
15
excellent question.
16
This is one of the reasons why
But I acknowledge that it is an
DR. DRAKE:
Dr. Siegfried?
I'm sorry.
17
Dr. Bergfeld, you had a question first.
18
apologize.
19
We look
DR. BERGFELD:
I
I speak as a
20
dermatopathologist now.
On the biopsies from the
21
atopic dermatitis group, we see a lot of spongiotic
22
dermatitis with eosinophils.
This is very similar
A Matter of Record (301) 890-4188
60
1 2 3 4
to what we see with contact dermatitis. We also see it in pynginitis [ph] occasionally with a lot of Staph. I'm not sure the lack of information proves
5
it doesn't exist, that these individuals have an
6
allergic response that's being expressed.
7
very similar to other things that we treat.
8
not going to let you dismiss the antihistamines and
9
the bacterial control on these skins.
10
DR. DRAKE:
11
DR. SIEGFRIED:
It's So I'm
Dr. Siegfried? With regard to the BPCA,
12
dermatology was selected as an area of interest in
13
2012, and we actually did raise those issues about
14
the importance of studying some of these medicines
15
that are already off-label.
16
funding, is the problem, I think.
17
DR. DRAKE:
There's lack of
So what I'm hearing as we go
18
through the discussion -- I'll do a summary at the
19
end as requested.
20
just come out of this at the moment is there is a
21
strong point of lack of convergence of opinion on
22
the role of antihistamines in this disease, at
I think one of the things that
A Matter of Record (301) 890-4188
61
1
least if you compare it with what you see
2
histologically, with other diseases that have an
3
allergic basis.
4
what I'm just hearing?
Is that a correct assumption of
That may be a point that we should look at
5 6
or talk about in the future.
I'm just trying to
7
gather -- this is different than most committee
8
meetings in that we're not trying to approve or
9
disprove a drug.
We're trying to get ideas here,
10
and so this discussion -- by the way, thank you for
11
pushing back.
12
on the table, is a little push and pull.
13
very much.
16
you.
Thank you
It's a good start.
Other comments on this?
14 15
I think that's how we get good stuff
Dr. Brittain, it's
Okay. DR. BRITTAIN:
Kind of shifting gears here,
17
in terms of the question about thinking about the
18
pediatric issue when you have adult data, I mean I
19
assume this must come up in other parts of the FDA.
20
I wonder how that's handled, and also are
21
there examples where there's been studies that
22
showed efficacy in adults?
You mentioned the issue
A Matter of Record (301) 890-4188
62
1
of differential safety, but have there also been
2
examples where there's efficacy in adults, and
3
there's no longer efficacy in children.
4
there are dosing issues as well because of
5
different sizes, et cetera?
6
DR. DRAKE:
7
DR. SIEGFRIED:
And maybe
Yes, Dr. Siegfried? I think one of the unique
8
things about atopic dermatitis is it's primarily a
9
disease of children with the biggest presentation,
10
so it's hard to draw analogies for other conditions
11
like psoriasis, which mostly presents in adulthood.
12
We say in pediatrics something like 60 percent of
13
drugs don't have pediatric labeling, but in
14
pediatric dermatology, it's probably more like
15
90 percent. DR. DRAKE:
16 17 18
on.
Excuse me.
I'm sorry.
I didn't have my mic
Michelle?
DR. ROTH-CLINE:
Just to respond to your
19
question, yes, this comes up all the time in
20
pediatrics, at the agency.
21
pediatrics and a part of the pediatric review
22
committee here, when there are studies that come
We, I think who work in
A Matter of Record (301) 890-4188
63
1
in, as was mentioned for adult indications, then
2
there is in some cases a requirement where we can
3
require pediatric studies.
4
But there are long discussions about the
5
circumstances under which we should do that and
6
when those studies ought to be conducted,
7
especially relative to the adult development
8
program.
9
that a little bit later in my talk.
10
I think I'm going to get into some of Certainly, if
I don't address some of that, please follow up.
11
DR. DRAKE:
12
DR. KATZ:
Yes.
Dr. Katz?
Ken Katz again.
Yes, I think it
13
might also be a special case for atopic dermatitis
14
in that atopic dermatitis can be the harbinger of
15
what was called the atopic march to allergic
16
rhinitis and to asthma, to food allergies.
17
It's possible that if you intervene early
18
enough, you might avert some of those diseases,
19
which hepatitis C, you treat hepatitis C in an
20
adult, you clear the infection; you treat hepatitis
21
C in a kid, you clear the infection.
22
But there could be an actual bonus actually
A Matter of Record (301) 890-4188
64
1
in terms of efficacy, the safety issues
2
notwithstanding.
3
research.
4
I think that supports more of
DR. DRAKE:
I have a question.
You just
5
said something interesting because I noticed it was
6
on slide -- on page 29, the slide on page 29, where
7
it looked like you had more AE's with -- help me.
8 9
Let's look at that. note of it.
I just made a quick
On page 29 -- somebody help me out
10
here -- was where you had more AE's with
11
the -- which bears, Ken, I think a little bit to
12
what you just said.
13
It had to do with it -- was it 27?
14
DR. LIEDTKA:
15
DR. DRAKE:
I wrote the wrong page down.
It was in the dupilumab group. Yes, it's on page 27, if you
16
look at that slide.
The SAEs were -- you had more
17
SAEs in placebo than you did on the dupilumab, so I
18
guess I was -- I thought that was an interesting
19
piece of data.
20
with -- I mean, one could jump and say maybe it was
21
more AEs with people who aren't treated, who aren't
22
getting response to therapy than there are with
The AEs may be more associated
A Matter of Record (301) 890-4188
65
1
people who are treated.
2
discussion.
3
I think that bears on the
When we're talking about risk-benefit ratio,
4
should we may be considering maybe a higher profile
5
type drug intervention to avoid some of the more
6
common SAEs or not?
7
would put before the committee for your
8
consideration because that slide struck me as being
9
kind of unusual.
I think that's a question I
10
Now, I think Elaine, you had a comment?
11
DR. SIEGFRIED:
In follow-up to your
12
comment, it speaks to the need for a study that
13
doesn't include a placebo arm.
14
something that definitely the committee needs to
15
address.
16
I think that's
The other thing I just did want to point
17
out, I think it's kind of ironic that the only
18
systemic drug that has FDA-approved labeling for
19
this disease has no data, and it's actually a
20
relative contraindication for long-term use
21
certainly that the guidelines recommend against
22
using that drug.
A Matter of Record (301) 890-4188
66
Then the other thing about new drug
1 2
development in kids, and particularly including
3
kids early on, is that if you just have an adult
4
study and it doesn't show lack of efficacy, there's
5
safety, but there's lack of efficacy.
6
mean that it'll have lack of efficacy in children.
It doesn't
7
The issue of long-term prevention of the
8
atopic march as well as improved efficacy in the
9
pediatric population is something that I think we
10
should discuss, too. DR. DRAKE:
11
Dr. Cohen?
And then I'm going
12
to take the prerogative of chair.
13
change the agenda here, the order just a little
14
bit.
15
I'm going to
But go ahead, Dr. Cohen. DR. COHEN:
I'm just going to make one quick
16
comment, and that is that a major issue for us in
17
the pediatric population is growth and development,
18
which is not an issue in most adults, at least
19
adults who are growing and developing --
20
DR. DRAKE:
That's a good counter --
21
DR. COHEN:
-- growth and development.
22
toxicities, which are a major issue for us with
A Matter of Record (301) 890-4188
The
67
1
many of these agents, are also issues in terms of
2
normal growth and development.
3
the risk-benefit ratios here, this is something
4
that's not an issue in adults but a major issue in
5
kids because clearly, atopic dermatitis can
6
interfere, especially those with moderate to severe
7
disease with growth and development.
8 9
So when we look at
So a lot of these parameters, you can be balancing efficacy with toxicity, and it's going to
10
be more important to look at special issues in the
11
pediatric population.
12
DR. DRAKE:
That's why I agreed to chair the
13
committee.
14
pediatricians here because I felt that there are
15
these kinds of considerations that just in pure
16
dermatology we all consider.
17
I insisted that we have honest to God
I worked my way through medical school as a
18
pediatric extern, and I can tell you there's a
19
whole different set of considerations there.
20
developed a healthy respect for understanding that
21
little guys behave differently than big guys.
22
I
I think that's our issue here today, is how
A Matter of Record (301) 890-4188
68
1
do we equilibrate the two so that we maximize it
2
for the little ones and not harm them, because
3
that's our goal, is to not cause any harm. Let me tell you what I'm going to do with
4 5
the schedule, just so you know.
6
these questions -- I think it will be helped if I
7
change the order where I'm not going to do a break
8
at 2.
9
and a break at 4.
10 11
I think some of
The reason is because there's a break at 2 I'm not ready to break.
Does anybody feel like they're in a desperate need?
12
(No response.)
13
DR. DRAKE:
Okay.
Because what I'm going to
14
do is we're going to go on and have the industry
15
present, too, okay?
16
presents, then we'll break.
17
And then right after industry
Then after that, we'll have the open
18
hearing, and then we can -- I think we'll have a
19
better discussion if we have all the information.
20
Let's get more information in front of us.
21 22
Is that all right with the committee? guess what I'm trying to ask, do I hear any
A Matter of Record (301) 890-4188
I
69
1
objection to that?
2
(No response.)
3
DR. DRAKE:
4 5
Okay.
Then that's the way we'll
go. Anything else on the FDA before I
6
move -- and industry, I hope you're ready to go
7
because I'm going to move straight to you, if
8
that's all right.
9
Okay.
So we'll move straight to industry.
10
I'm sorry.
What?
11
apologize.
I didn't see you.
12
Oh, I'm sorry.
DR. KOPELMAN:
Excuse me.
Thank you.
I
Please.
I wanted to be clear.
In
13
future testing, given that there's a risk-benefit
14
in whether you use other systemics, or other
15
whether you use cortico creams, or whether you use
16
a new biologic, are you thinking of testing against
17
these other therapies or are you thinking about
18
testing against placebo?
19
Maybe it'll become clearer as we go on.
20
DR. DRAKE:
That isn't clear to me.
Unless somebody has a really
21
good answer for that right now, we could go on and
22
see -- because I think you've hit on -- I mean,
A Matter of Record (301) 890-4188
70
1
yes, that's the issue of the discussion.
2
you guys are zeroing right in on the point of it. Thank you.
3 4 5
Okay. DR. MALONEY:
Why don't you go on?
We don't
want to miss Dr. Roth-Cline's presentation. DR. DRAKE:
8 9
Dr. Maloney, you just asked –
sideline, you just asked me a quick question.
6 7
I mean
then.
All right.
We will move forward
Let's let you go ahead and talk.
We'll go
10
through the industry, and then we can have more
11
discussion because it'll just put more of the
12
issues on the table for us to consider and
13
additional perspectives.
14 15
Industry Presentation – Rene van der Merwe DR. VAN DER MERWE:
Good afternoon,
16
everybody.
17
with Medimmune.
18
Gianella-Borradori, will be presenting Medimmune
19
and Chugai from the industry.
20
My name is Rene van der Merwe.
I'm
My colleague and I, Dr. Athos
The overview of atopic dermatitis was very
21
well covered by Dr. Lindstrom, and lots of my
22
presentation will probably just cover that, but
A Matter of Record (301) 890-4188
71
1
mainly from a slightly different perspective with a
2
view on clinical development of atopic dermatitis,
3
especially in this pediatric population that's not
4
responding to topical steroids or other topical
5
therapies.
6
So as Dr. Lindstrom alluded to, it's a
7
chronic inflammatory itchy skin condition, and it's
8
probably the most common skin condition in the
9
pediatric population.
It manifests as these
10
papules that you saw on the slides previously and
11
also on this one, too, and it's relapsing and
12
remitting.
13
quality of life for, not only the patients but the
14
carers and the parents as well.
15
This disease does cause a severe
One thing that was very significant to me
16
that Dr. Lindstrom alluded to was the time it takes
17
to treat these patients.
18
them are looked after with topical emollients, very
19
strict skin care regimes, and this all takes a lot
20
of time.
21
really is a great stress, too.
22
I mean the majority of
In a very busy family situation, it
But the scratch-itch cycle is also very
A Matter of Record (301) 890-4188
72
1
significant because this is what causes the skin
2
barrier damage but also the infection risk.
3
as Dr. Lindstrom again alluded to, these children
4
do have an increased susceptibility to infections,
5
not only bacterial but also viral and fungal.
6
These,
There's a very much a complex interaction of
7
genetic, immunological, and environmental factors,
8
which initiate and progress the atopic dermatitis.
9
The lesional skin is characterized by this impaired
10
skin barrier that I mentioned, also a deficient
11
innate immune response and predominantly a TH2
12
mediated inflammation.
13
have elevated IgE serum levels.
14
Many of these children will
The common dermatitis triggers are
15
irritants, allergens, microbes and climatic
16
factors.
17
dermatitis, we're unsure of what the role is of
18
these factors and the severity in atopic
19
dermatitis.
20
Although they do trigger atopic
We've been mentioning a lot about the atopic
21
dermatitis -- well, the atopic march and very much
22
in children, you have this sequence that occurs in
A Matter of Record (301) 890-4188
73
1
allergies and symptoms.
Also, what Dr. Katz was
2
alluding to that if we intervened earlier on, would
3
we then be able to stop that march?
4
Often, atopic dermatitis is probably the
5
first disease or allergic disease to manifest in
6
the march.
7
develop skin allergies, food allergies, allergic
8
rhinitis, and asthma as well.
Often, these children will go on to
I think we all gathered here because we know
9 10
that it's going to become -- it is a disease
11
burden.
12
to us with a prevalence of atopic dermatitis
13
increasing especially in children.
14
It's becoming a very gray disease burden
Although 80 percent of you as children have
15
atopic dermatitis, the majority of these are
16
probably very mild and transient.
17
cases will also improve during childhood and go
18
into remission by the time these children reach
19
adulthood.
20
Many of these
What's very important is that children
21
develop it by 6 months to 5 years.
22
having spontaneous remission, they do still have to
A Matter of Record (301) 890-4188
Despite them
74
1 2
be treated in that time period. There's evidence that suggest that
3
prevalence of AD decreases as the age increases,
4
and Silverberg and Simpson analyzed data from the
5
2007 National Survey of Children's Health.
6
looked at this, and they also saw that the children
7
with more severe disease were more likely to have a
8
protracted disease course and a worse quality of
9
life compared with those that had mild disease.
10
They
Again, very little data are available
11
looking at atopic dermatitis, the prevalence of AD,
12
but also those who are inadequately treated with
13
topical or systemic treatments.
14
Silverberg and Simpson analyzed the data of
15
the study I mentioned before, and they showed that
16
about 67 percent had mild disease, 26 percent had
17
moderate disease, and about 8 percent had severe
18
disease.
19
Also, because the data is so sparse, we can
20
extrapolate that from this that a proportion of
21
these subjects that had moderate disease who were
22
on the topical therapies would probably fall in the
A Matter of Record (301) 890-4188
75
1
moderate group and those on systemic
2
treatments -- and I refer to systemic treatments
3
here as immunomodulatory agents rather than any
4
other systemic treatment -- would probably fall
5
into the more severe group. One thing that is not really that obvious
6 7
but that is shown here in this data from Silverberg
8
and Simpson is as I mentioned earlier that as the
9
age increases, the prevalence decreases. But what you can see here clearly is that
10 11
the severity increases so much so that the age
12
group between 7-17 years have 8-9 percent have the
13
severe disease.
14
of U.S. children.
That's equivalent to 0.6 million
15
Age-related differences in the disease
16
manifestation -- Dr. Lindstrom alluded to this
17
earlier as well -- it occurs in three main
18
age-related stages.
19
overarching symptom and appears in all of these
20
stages.
21
damage and the worst quality of life.
22
But pruritis is the
It's also the one that causes the most
In infants, they have red, scaly, crusted,
A Matter of Record (301) 890-4188
76
1
weeping patches on their cheeks and extensor
2
surfaces as you saw in the photographs from
3
Dr. Lindstrom.
4
In childhood, they have plaques, papules,
5
and also in the flexural surfaces.
6
adults -- and I've put adults and adolescents here
7
together because the symptoms are very, very
8
similar in the flexural surfaces, the face and
9
hands and feet.
10
But in
I think one thing that has become clear very
11
much as we, as an industry, started writing the
12
briefing document was that how little data were
13
available on the prevalence, but also the
14
treatment.
15
definitions of atopic dermatitis, the lack of
16
universally-accepted of inadequate response, what
17
does it mean?
18
And then going down into the
The European Academy of Dermatology defines
19
inadequate response as those patients that have
20
been treated for 2 weeks and have had no
21
improvement in symptoms.
22
fully cover the entire spectrum of inadequate
But this doesn't really
A Matter of Record (301) 890-4188
77
1
response because you have some patients who do
2
respond to topical steroids, but they need such a
3
high dose or such a high potency of steroids or for
4
such a long frequency that it does then become a
5
problem, and they can't remain on that.
6
something to help treat those children as well.
7
So we need
Other challenges that we're faced with as
8
industry -- because how do we prove efficacy and
9
safety -- are the disease severity scale.
There
10
are a number of disease severity scales out there
11
but there's no gold standard identified.
12
Common scales that have been used or the
13
EASI and the SCORAD, you saw earlier on the
14
dupilumab data using the EASI.
15
the physician, an objective assessment of the
16
physician looking at the extent and severity of the
17
disease, SCORAD looks at the objective assessment
18
of disease severity and extent, but also includes a
19
subjective measure of the patient-reported sleep
20
and itch.
21 22
Where EASI looks at
Other measures that are there, the IGA and the SASSAD -- and with the IGA, it's not a very
A Matter of Record (301) 890-4188
78
1
sensitive measure because it's either zero, or 1,
2
or 2 or 3.
3
then, they may be zero or they may be 1.
4
lot of inconsistency in rating these scales.
5
If somebody has a very small patch There's a
But not only the inconsistency in the rating
6
or the sensitiveness of these is the
7
standardization of these scales as well.
8
uniformity in the scale exists, and the
9
differences, requirements by the different health
10 11
Lack of
authorities as well. I won't go into this in very much detail as
12
Dr. Lindstrom covered it.
13
the AAD don't differentiate in the treatment
14
modalities between adults and pediatrics.
15
mentioned earlier, there's no FDA-approved
16
treatment for patients with AD except for
17
corticosteroids, which is not recommended.
18
Again, but in general,
As she
Again, the majority of these patients,
19
especially the milder group, are treated at home
20
with good skin care regimes, emollients, topical
21
therapies whether that's corticosteroids or
22
calcineurin inhibitors but also lifestyle
A Matter of Record (301) 890-4188
79
1 2
environmental modifications. If these methods, if they're not controlled
3
by the previous methods, then phototherapy is
4
recommended as well.
5
little long-term safety data showing the
6
risk-benefit of phototherapy in children.
7
But again, there's very
Systemic corticosteroids, we've spoken about
8
earlier so I won't go into detail about that again.
9
But where it can be used is for the management of
10
comorbid conditions, example, severe asthma or
11
asthma exacerbations.
12
Again, systemic immunomodulating agents are
13
recommended.
14
European Union for the treatment of atopic
15
dermatitis and has also shown that it does have an
16
effect on symptoms, extensive disease, not
17
comorbidities, but quality of life and pruritis,
18
both in treating short- and long-term studies.
19
Cyclosporine A is recommended by the
Azathioprine has also been recommended by
20
the American Academy of Dermatology for
21
recalcitrant atopic dermatitis.
22
Dr. Lindstrom showed the effects that were seen in
A Matter of Record (301) 890-4188
Again,
80
1
subjects treated with azathioprine. Methotrexate is also recommended by the AAD.
2 3
However, the effect on atopic dermatitis is
4
inconsistent due to the different study designs,
5
treatment durations in the control trials that have
6
been done. Mycophenolate mofetil has also been
7 8
recommended.
But again, there's some inconsistency
9
and unclear effect in pediatrics.
But the AAD do
10
recommend, and I quote, "should be considered a
11
relatively safe and alternative systemic therapy
12
for the pediatric patients with refractory AD." Again, I think we're all very aware that the
13 14
systemic agents used, or the immunomodulating
15
systemic agents used, to treat atopic dermatitis
16
have a very large safety database in pediatric
17
populations as well but they don't go without
18
risks.
19
risks in pediatric patients.
20
They all have black box warnings and severe
Cyclosporine, here again, the risk of
21
infection, malignancy, gingival hyperplasia, which
22
is also a very bad side effect for these children,
A Matter of Record (301) 890-4188
81
1
and sometimes even have to undergo surgery when
2
they've had that.
3
immunosuppression with malignancy risk, infection
4
risk, hepatotoxicity and bone marrow suppression is
5
also very important.
Azathioprine, chronic
6
Methotrexate, again, bone marrow
7
suppression, skin and kidney toxicities, and can
8
cause pancytopenia, elevated transaminases, and
9
liver fibrosis.
Mycophenolate mofetil, the main
10
effects here are GI effects with nausea, vomiting,
11
diarrhea but they can also have leukopenia and
12
hypertension.
13 14 15 16
With that, I'll pass you over to my colleague. Industry Presentation – Athos Gianella-Borradori DR. GIANELLA-BORRADORI:
Thank you, and good
17
afternoon.
The adverse event list actually gives
18
us a good transition point for the following
19
consideration on the potential concerns on
20
developing the new agents in this population, new
21
agents which mainly are --
22
DR. DRAKE:
Excuse me, sir.
A Matter of Record (301) 890-4188
I might've just
82
1
missed it.
2
identifying not only your name but what your role.
3
I apologize.
But would you mind
DR. GIANELLA-BORRADORI:
I'm Athos Gianella-
4
Borradori.
5
oncologist.
6
Chugai is one of the largest pharmaceutical
7
companies in Japan.
8
to most of you in the U.S.
9
any product in the U.S.
10 11 12 13
I am a pediatric hematologistI am chief medical officer at Chugai.
I think it's largely unknown We don't commercialize
We only perform clinical
and basic research. DR. DRAKE:
Thank you very much.
It's very
helpful. DR. GIANELLA-BORRADORI:
Thank you for
14
allowing me to do that.
15
that the list of the adverse events of the
16
well-known therapies have been around for many
17
years and have been used for the treatment of these
18
children.
19
So I started by saying
It offered me a good opportunity, and it's a
20
good bridge to move into the consideration we have
21
made on how to optimally time the development of
22
new agents for these children.
A Matter of Record (301) 890-4188
83
New agents.
1
And I think it's interesting to
2
see, most of these new agents are actually first-
3
in-class.
4
molecules; most of them are molecular target.
5
by being first-in-class, they likely don't come
6
with the baggage of both scientific and clinical
7
knowledge that many of the available agents or
8
non-first-in-class agents actually have.
These are agents that targets new And
We started our work by analyzing 2 sets of
9 10
data.
We looked at the recent experience in
11
approving biologics in psoriasis, and we looked at
12
the available regulations.
13
example of the TNF approval, which is actually
14
quite interesting.
Here, we found an
15
Here, the risk of malignancies in adult was
16
identified from clinical trials that were performed
17
who gave results after the initial approval.
18
fact, there was evidence emerging that treatment
19
with TNF blocker in children may actually increase
20
the risk of malignancies and increase it quite
21
significantly, up to 4 times the estimated
22
background rate in the general U.S. population.
A Matter of Record (301) 890-4188
In
84
1
Based on this, obviously, it seems that for
2
some agents at least, it's appropriate to complete
3
an adult safety evaluation before actually starting
4
the use of these agents in children.
5
lesson wasn't applied when a couple of months ago,
6
the FDA, the approval letter for Cosentyx was
7
published.
8 9
Perhaps this
This letter, as we can see, says that zero safety signals have been observed in adults, and
10
the agency determined that pediatric studies should
11
be deferred until after adult studies have been
12
completed.
13
Now, we all go from birth to adulthood
14
through different stages of development.
15
one of these stages, of these periods, has its own
16
sensitivities, and its own organs that can be
17
particularly sensitive to systemic agents or to
18
systemic therapy, both infancy, preschool years,
19
middle school years, adolescence.
20
these periods, there is an organ system that
21
develops and can be sensitive.
22
Each of
In each one of
The overall rule has been to take great
A Matter of Record (301) 890-4188
85
1
care, not to negatively impact the normal growth
2
and development process throughout these stages.
3
And certainly, one of our great interests has been
4
to ensure that the immune system develops normally
5
during these phases.
6
As you know, neutrophils mature during
7
infancy, and that's a period where the cells
8
clearly have to be allowed to develop strongly.
9
The innate immune system maturation proceeds very
10
rapidly in the preschool years but then continues
11
to develop and reaches almost capacity by
12
adolescence.
13
While the adaptive immune system actually
14
continues to develop throughout life.
And although
15
it's shaped greatly during the pediatric years, it
16
continues to develop later on.
17
Now, with these, both information from past
18
history and this introduction of biology, we added,
19
for our consideration, the available regulations.
20
On one side, we find the Code of Federal
21
Regulations, a clear indication on the pediatric
22
safeguards.
A Matter of Record (301) 890-4188
86
1
The text here reads that potential risks
2
posed by novel agents, and particularly
3
immunomodulatory agents, generally exceed in minor
4
increase or minimal risk.
5
There is, as in many other places of
6
regulations on both sides of the Atlantic, the
7
principle that risk should be justified by the
8
anticipated benefit, and therefore an important
9
element of every evaluation is the risk-benefit
10 11
assessment. The availability of alternative therapies,
12
again, it's something which comes into the equation
13
when one considers the risk-benefit, the overall
14
risk-benefit assessment of testing new systemic
15
agents in the pediatric population.
16
ICH E11, also here, we find precise guidance
17
on when and how to time pediatric studies.
18
spells out that the timing depends on the type of
19
medicinal product or the type of the disease,
20
safety consideration, and the availability of
21
alternatives.
22
ICH
AD, we've heard it today, and it's the
A Matter of Record (301) 890-4188
87
1
reason why we're here today, is clearly a disease
2
that, in children, can be severe and debilitating.
3
There is clearly a medical need for children to
4
have access novel science-driven systemic
5
therapies. Safety, there are certainly many
6 7
uncertainties, especially for first-in-class
8
agents.
9
not enough to justify exposing children to the risk
10 11
We may know little, and for some people
or to the potential benefits of the agents. Alternative therapies, again, they are
12
recommended quite extensively.
13
years of experience.
14
and they're used without, sometimes, clear guidance
15
on how to dose them and how to adapt the dose to
16
the efficacy and/or to the adverse effects of the
17
children.
18
There are many
They are not satisfactory,
These are treatments where the risks are
19
well-known, and where benefits are unknown but
20
sometimes are a bit controversial.
21
Now, I think while recognizing that there
22
are framework both from a regulatory perspective,
A Matter of Record (301) 890-4188
88
1
from an ethical perspective, and also from a
2
patient perspective, I think we are here today, and
3
we all agree that there is clearly a need to do
4
more, and to find ways to accelerate, in a safe and
5
acceptable way, the development of new systemic
6
agents for these children.
7
compromised.
8
balance.
9
Again, safety cannot be
At the same time, we have to find the
Perhaps one way forward this to look at this
10
algorithm developed by Dunne and colleagues in
11
2011, which is actually quite a helpful, at least
12
for me, quite a helpful way of looking at the issue
13
and find positive, quick outcomes.
14
The three options here are very much based
15
on the fact that certain diseases in children and
16
in adults are very similar, that the response on
17
intervention can very similar between children and
18
adults; and in some condition, pharmacokinetic and
19
pharmacodynamics can be very similar between adults
20
and children, or not.
21 22
Then obviously, we go down the right path with option C if everything is similar between
A Matter of Record (301) 890-4188
89
1
adult and children, or we go down on the left side
2
towards option A or option B where there are
3
significant differences.
4
having an acceleration of the development, we
5
actually have a sequential development or a
6
parallel full development of adult and children,
7
and not very much in acceleration.
8
And then instead of
Now, if we try to apply this algorithm to
9
the current situation in AD, one can argue that if
10
extrapolation can be based on exposure-response or
11
on PK/PD, in where indeed the disease between
12
adults and children is similar in it presentation
13
and its course, well, then there is the potential
14
to submit pediatric safety data at the time as the
15
adult data, and submit for approval.
16
If extrapolation is not possible, well, then
17
both safety and efficacy trials would be required
18
for the pediatric population and to obtain a
19
pediatric label.
20
Which basically leads to these
21
considerations for the timing of pediatric study:
22
having the knowledge that the need is there and
A Matter of Record (301) 890-4188
90
1
having the knowledge that children with AD -- a
2
certain percent of children with AD today that do
3
not respond to topical therapies.
4
Well, then what we consider the adolescents,
5
these are children over the age of 12, can actually
6
be studied together with adults in the same
7
studies.
8
the population can be considered very similar to
9
the disease of adults in terms of manifestation and
The reason here is that the disease in
10
evolution.
11
atopic diseases has very much started in these
12
adolescents the same way as it starts in adults.
13
The march of allergies or the march of
It can be a bit different for children below
14
the age of 12 where the timing probably can be a
15
bit more careful because the disease can be
16
somewhat different, because the march has not
17
really started yet or can still be erratic, and
18
because in certain number of these children, it can
19
go into spontaneous remission.
20
I think it boils down very much to a
21
case-by-case consideration.
We have variables from
22
the age, variables from the biology of the child,
A Matter of Record (301) 890-4188
91
1
and there is risk-benefit profile that will change
2
very much based on the type of age, condition and
3
the agent.
4
Clearly, having data available to support
5
the risk and the benefit from adults would help a
6
lot improving or having a better risk-benefit
7
assessment of children.
8
molecule or biologic, again can make a big
9
difference on how much we can or we dare to
10 11
The type of drugs, small
extrapolate in their supposed safety and efficacy. We've seen the alternative therapies.
12
Again, they're not optimal but they are there.
13
in skilled hands, sometimes they can do very well.
14
As I mentioned before, the younger
15
population, and here again, there are practical
16
considerations in the time you'd need to recruit
17
these patients, not only their disease can be
18
variable over time with higher remission rates,
19
sometimes the diagnosis is quite difficult.
20
And
Last but not the least, sometimes parents
21
can be quite reluctant to allow their young
22
children to enter into trials testing drugs.
A Matter of Record (301) 890-4188
92
1
This brings us to the consideration to the
2
final slide of the consideration where we would
3
like to suggest the possibility that adolescents
4
can be included in pivotal studies for registration
5
of agents for the systemic treatment of subjects
6
with atopic dermatitis.
7
Subjects or children between the ages of 2
8
to 12 year olds should be deferred, and their
9
studies may be started once there is a good
10
understanding of the potential risk or there is
11
more understanding of the risk of exposing this
12
younger population with new agents.
13
The under 2 year old could actually be
14
subject for a waiver for clinical development.
15
the reason here could from one side an ICH concern
16
or an ICH statement about the unpredictable effects
17
in pediatrics under the age of 2 for biologics, and
18
then the fact that these studies actually be
19
impractical in terms of how they are performed.
20
And
Not only impractical because of the number
21
of children that could be available for studies but
22
also impractical because the disease can have a
A Matter of Record (301) 890-4188
93
1
high rate of spontaneous remission like up to 70
2
percent of the 2 year olds may actually have a
3
spontaneous remission of AD.
4
can be highly variable.
5
parents could actually be sometimes reluctant to
6
include their young children in these type of
7
studies.
8
The clinical course
And as I mentioned before,
This brings me to the last slide summarizing
9
very much what we said in the last half hour.
10
think we all recognize the need for effective
11
therapies for children that inadequately respond to
12
topical therapies.
13
science and in practical aspect, the timing of
14
pediatric studies should be considered very much on
15
a case-by-case basis based on a risk-benefit of
16
each product.
17
I
We think that based both on
I think the good or the great news is that
18
there are a number of novel therapies out there
19
being tested, and they offer the opportunity to
20
provide safe and effective therapies to patients in
21
the near future.
22
and thank you for the attention.
On this optimistic note, I close,
A Matter of Record (301) 890-4188
94
Clarifying Questions
1
DR. DRAKE:
2
Thank you very much.
Let's take
3
a few minutes and see if there are any clarifying
4
questions for our industry's folks.
5
sorry.
6
just pointed to you.
7
name so that the record knows who's talking.
8
you.
9
I should've said Kopelman.
DR. KOPELMAN:
Yes?
I'm
I'm sorry.
I
Remember, please state your
Loretta Kopelman.
Thank
You
10
recommended testing the over 12 group with the
11
adults and deferring on the 2 to 12 year olds.
12
What recommendation would you have or what insight
13
would you have about the danger of the drug just
14
being used off-label in the most vulnerable group,
15
the under-12, if one should get approval?
16
DR. GIANELLA-BORRADORI:
Well, the under-12
17
could actually be tested during -- the deferral
18
just means not doing it at the same time.
19
be delayed.
20
DR. KOPELMAN:
It would
Well, then would you wait for
21
that testing and then get approval, one approval
22
all at once, or would you want approval for the
A Matter of Record (301) 890-4188
95
1 2 3
over-12s? DR. GIANELLA-BORRADORI:
The idea would have
to have approval for the over-12 and adults.
4
DR. KOPELMAN:
And then my question is --
5
DR. GIANELLA-BORRADORI:
And then slightly
6
delayed, but it does not mean really in pure
7
succession.
8
may have sufficient data to justify taking the risk
9
of 2 to 12.
10 11 12
Let's say at the end of phase 2, one
DR. KOPELMAN:
I see.
So you would want to
begin at the end of phase 2 with the younger group. DR. GIANELLA-BORRADORI:
For example, yes.
13
As soon as there is enough data that makes
14
everybody comfortable, we have a good understanding
15
of the risk-benefit profile, and now we go into a
16
more vulnerable population because of its biology.
17
DR. KOPELMAN:
18
DR. DRAKE:
19
DR. KATZ:
I see.
Thank you.
Dr. Katz? Ken Katz.
I have a question
20
about the choice of age 12.
I'm just not clear on
21
where that's coming from.
22
elaborate on the data that suggests that's a
Maybe you could
A Matter of Record (301) 890-4188
96
1
tipping point in terms of natural history. Also, on that point, I think you mentioned
2 3
that atopic march in adolescents is similar to
4
adults.
5
much before that, in the younger age group.
6
maybe you can clarify those couple of points.
7
Thank you. DR. GIANELLA-BORRADORI:
8 9
I was thinking it's something that happens So
On the first part,
I have to pass to somebody else for the ICH.
On
10
the second thing about the similarities, we've seen
11
in the data before but indeed, towards adolescence,
12
we see more and more a similar pattern of severity
13
between adults and adolescents, and the percentage
14
of severe or moderate case becomes very similar
15
between adolescents and adults. I think although the pattern of disease,
16 17
with more lichenification, less oozing, less
18
bleeding, it's more typical of the adolescents and
19
the adults, while young children have more oozing,
20
more protein loss than adults or adolescents.
21
I may defer to the pediatric dermatologists in the
22
room.
They probably know much more than I do.
A Matter of Record (301) 890-4188
But
I'm
97
1
trying to improvise a bit here.
2
that.
3 4 5 6
DR. DRAKE:
Dr. van der Merwe, you have a
comment on that, and then back to you, Ken. DR. VAN DER MERWE:
I was just going to
answer the atopic march.
7
DR. DRAKE:
8
DR. VAN DER MERWE:
9
I'm sorry about
I think we need your mic on. Is it on?
Thank you.
was going to answer the atopic march.
I
I'm sorry
10
there may have been a misunderstanding.
11
referring to is that the atopic march does occur
12
very early on in childhood but as you mentioned, if
13
we do intervene much earlier, then we can stop that
14
whole disease, allergic -- not triad, but the whole
15
march and start earlier on.
16
What I was
What I was referring to -- I may have
17
misunderstood as well; and my apologies -- is that
18
the 12 year olds have a very similar disease state.
19
And that's where I think I may have confused or
20
misspoken.
21
very early on in childhood.
22
allergic and the symptoms start.
But no, definitely, the atopic march is That's where the
A Matter of Record (301) 890-4188
98
1
DR. DRAKE:
2
DR. KATZ:
Dr. Katz? I think we're talking about the
3
slide number 9, which shows severity in age ranges
4
from less than 1 year to up to 17 years, which
5
shows some differences.
6
to adults per se, so I'm just wondering -- maybe we
7
can think a little bit more about the epidemiology
8
and the natural history, and the extent to which
9
one group is similar or dissimilar from the other. DR. DRAKE:
10
Tell me again exactly -- I like
11
what you said.
12
down in a few words.
I'm just trying to synthesize it
DR. KATZ:
13
But there's no comparison
Help me again.
I'm still suggesting there might
14
be a lack of data that's been presented so far that
15
supports that -DR. DRAKE:
16
Okay.
17
concurrence on that.
18
issue.
19
I don't mean just here.
20
general.
21 22
We're in complete
Yes, I think that's the
We don't have a lot of data, I don't think. I mean I'm just saying in
You're exactly on target.
DR. BILKER: extrapolation.
Dr. Bilker?
I have a question about
It looks like extrapolation is used
A Matter of Record (301) 890-4188
99
1
for looking at efficacy going from older children
2
and adults to younger age groups but not
3
necessarily used for looking at safety in dosing.
4
But we know that a lot of these drugs are
5
given off-label, and I'm wondering if using any of
6
that information, what would that tell you about
7
how the extrapolation would have done?
8
words, has data been collected on that since these
9
patients are getting it anyway?
10 11
In other
Has data been
collected on that? DR. GIANELLA-BORRADORI:
Well, I guess we
12
can try the exercise by taking corticosteroids or
13
in AD I guess at the top -- well, the answer is
14
yes, right?
15
We expect the corticosteroids to have same
16
effect in children and adults, right, so go down to
17
the right, and it will now be option C.
18
yes, I mean we can use this algorithm to actually
19
test -- I can't say the validity, but test how
20
reasonable it is based on today's off-label use.
21
Is this your question?
22
DR. BILKER:
Right.
But I'm
A Matter of Record (301) 890-4188
I think
100
1
wondering -- no, I'm wondering what that actual
2
data -- children who are getting some of these
3
drugs off-label, how are they faring, and how would
4
the extrapolation have worked if it were used to
5
predict how they would have done?
6
DR. GIANELLA-BORRADORI:
Again, I think if
7
we use corticosteroids as an example, it works,
8
right, because it fulfills the criteria and it
9
brings I think to option C.
10 11
No?
Perhaps I
misunderstand your question? DR. VAN DER MERWE:
Athos, may I?
I think
12
the bottom line is the data isn't collected.
13
only reference we have to go on is if case reports
14
are published in journals.
15
collected and fed back to the individual
16
pharmaceutical companies.
17
because it's very valuable data.
18
DR. DRAKE:
Yes.
19
DR. ROTH-CLINE:
The
But the data isn't
And that is unfortunate
Dr. Cline? So if I can make a
20
clarification of that extrapolation and the
21
agency's use of extrapolation, this was a paper
22
that was published actually out of our office, the
A Matter of Record (301) 890-4188
101
1 2
Office of Pediatrics Therapeutics. Pediatric extrapolation.
And there's now at
3
FDA several different uses of the word
4
"extrapolation."
5
really a discussion of products that have not yet
6
been approved, typically, so that are still under
7
development.
8 9
But pediatric extrapolation is
The question is really about extrapolation of efficacy data from adults to children.
And we,
10
in pediatric extrapolation specifically, don't
11
extrapolate safety and don't extrapolate dosing,
12
because we have found actually in another article
13
that was published again by our office that very
14
frequently, there are pediatric-specific safety
15
concerns that cannot be predictive based on adult
16
data, number 1.
17
As well, that dosing is unpredictable, let's
18
say, from the typical either, weight-based or body
19
surface area-based dosing equations that one would
20
typically use.
21
specific to talking about efficacy in this
22
particular context.
So extrapolation is really very
A Matter of Record (301) 890-4188
102
1
However, your point about use data and
2
trying to understand some pediatric data about
3
products that are already marketed is well-taken.
4
But that's really a sort of separate issue from
5
extrapolation. DR. DRAKE:
6 7
Thank you.
8
my list?
Let's see.
Do I have anybody else on
Yes, Dr. Katz?
DR. KATZ:
9
That was actually helpful.
One more point at slide 24.
It
10
just seems that the case here might be slightly
11
overstated for the alternative therapies where it
12
says -- if the point is that benefits and risks are
13
known, I think really the point is that benefits
14
and risks of these other therapies are not known. We don't know enough about the dosing.
15
We
16
don't know enough about the safety profile.
17
seems like the case, against pediatric testing, is
18
somewhat overstated on the basis of that. DR. DRAKE:
19
Could be.
So it
I have a question,
20
too.
On slide 20, you said that there were serious
21
safety signals observed in adult patients
22
with -- well, what am I trying to say?
A Matter of Record (301) 890-4188
I chair
103
1
this panel.
You'd think I could say it.
2
(Laughter.)
3
DR. DRAKE:
4
DR. DiGIOVANNA:
5
DR. DRAKE:
Come on, John. Secukinumab.
That's it.
That's what I'm
6
trying to say.
I chair that panel.
You said there
7
were some serious safety signals that were
8
observed, and I guess I'm just curious what you
9
were referring to because we didn't find
10
really -- maybe the FDA can help me on this, too.
11
We didn't find any serious ones.
12
signals but I don't know if there were any that
13
were serious.
14
referring to maybe?
We found some
Could you tell me what you were
15
DR. GIANELLA-BORRADORI:
16
word by word from the approval letter.
17
DR. DRAKE:
18
guys referring to?
19
Well, this is taken
I figured it was so what are you
DR. MARCUS:
I would like to just emphasize
20
the word "signals" here.
And I think that what
21
this statement is referring to are the exposure-
22
related increases in certain infections and the
A Matter of Record (301) 890-4188
104
1
possibility that with long-term use, serious
2
adverse events related to infections would become
3
more apparent once the product has been marketed
4
for adults.
5
DR. DRAKE:
Good.
That was my recollection
6
but I just want to make sure there was nothing else
7
that we hadn't talked about or considered during
8
the panel discussion.
9
three people.
10
Thank you.
You, you, and you.
DR. TOWBIN:
Okay.
I got
How is that?
Thank you very much.
11
Kenneth Towbin.
12
think, 30 once again.
13
intention with your first bullet here about the
14
potential inclusion of adolescents with the adult
15
population.
16
because there may be age-specific side effect
17
profiles that you wouldn't want to just mix these
18
populations, that they would need to be studied in
19
a stratified way.
20
I'd like to go back to slide, I I think I understood your
But I just wanted to underscore that
Because of course, there would be the risk
21
that the number of adolescents, and perhaps being
22
smaller than the number of adults, might dilute a
A Matter of Record (301) 890-4188
105
1
side-effect profile that would be a signal in
2
adolescents.
3
The second point about this as we've been
4
talking is that the tail for the study of
5
adolescents, and in fact children and younger
6
children, would need to be much longer than the
7
tail for adults because of the concerns about an
8
accumulating risk for cancer or other kinds of
9
maladies down the line.
10
We really wouldn't want to just look at the
11
effects during the immediate treatment trial but
12
there would need to be some really long-term study
13
looking at the long-term side effects of these in a
14
developing population.
15
DR. DRAKE:
Dr. Maloney?
16
DR. MALONEY:
We've talked very briefly
17
about collecting data when medications are used
18
off-label in younger children or in children.
19
seems to me that those -- when that happens, you
20
don't have a controlled study so you actually can't
21
use that information for efficacy.
22
seem that if this data is collected, it can be used
A Matter of Record (301) 890-4188
It
But it does
106
1
for safety data. What we need is an effective way to collect
2 3
that data for safety so that we then can develop
4
the control trials for efficacy, feeling much more
5
comfortable, since my concept of this panel is that
6
we all feel really uncomfortable having trials in
7
kids. We don't want to hurt kids with trials.
8 9
And
so if we've collected safety data in other ways, we
10
all would sleep better at night, this from a Mohs
11
surgeon, not a pediatric dermatologist.
12
totally off base?
I just threw that out there.
DR. DRAKE:
13
Am I
No.
I think it's a good point.
14
My question back would be -- first, you have to get
15
people to report it, which -DR. MALONEY:
16
Well, that involves setting up
17
a very robust reporting.
And the people who are
18
using this drug, these drugs off-label do have a
19
tremendous investment.
20
dermatologists around the table who use these drugs
21
in the sickest kids have the greatest impetus to do
22
this.
I mean all of you pediatric
A Matter of Record (301) 890-4188
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1
DR. DRAKE:
Dr. DiGiovanna?
2
DR. DiGIOVANNA:
I wanted to go back to
3
Lynn's question about secukinumab, not because I
4
was finally able to pronounce it after training.
5
I'd like to understand since we were at the meeting
6
exactly what this means about deferring the studies
7
since this was dated January 15th.
8
Does that mean that they are ongoing, that
9
they will be ongoing or when will they be ongoing?
10
How does this actually work for a drug that's now
11
recently been approved?
12 13 14
DR. DRAKE:
I'm going to pass that to -- in
a moment, right? DR. MARCUS:
Yes.
Currently, there
15
are -- and I'm going to have to look to the back of
16
the room here just for a nod of yes or no.
17
not have clinical trials ongoing in pediatric
18
populations for secukinumab at this point.
19
We do
At the current time, we're really waiting
20
for some accumulation of adult data and the
21
deferral -- yes, I don't have the letter in front
22
of me, so I'm having the actual deferral time
A Matter of Record (301) 890-4188
108
1 2
scribbled on a notepad next to me. We're currently deferring this for eight
3
years post-marketing for adults in order to collect
4
additional data from pharmacovigilance in adults.
5
At the time of marketing approval for secukinumab,
6
it was felt that this would be a sufficient period
7
of time to collect adequate data to move forward
8
with pediatric study.
9 10
DR. DRAKE:
I think, Dr. Cline, you had a
comment directly related to that, right?
11
DR. ROTH-CLINE:
12
to explain what a deferral is.
13
a BLA or a new drug application or a biological
14
licensing application is submitted to the agency
15
for, let's say, an adult indication or for an
16
indication in 12 or older, whatever the age group
17
is that is covered under the application.
18
Yes.
Just a quick comment A deferral is when
Pediatric studies in younger age groups
19
under the law can be either waived or deferred
20
depending on the circumstances.
21
the example was given here, might be considered in
22
patients where the disease really doesn't occur;
A Matter of Record (301) 890-4188
So a waiver, as
109
1
there are several other conditions under which a
2
waiver can be considered.
3
A deferral is a deferral for an unspecified
4
by -- it's specified at the time of the approval as
5
to how deferred the pediatric studies are.
6
be that the pediatric studies are actually ongoing
7
at the time of the initial marketing approval of
8
the drug in adults, and they're simply not
9
completed yet, and the sponsor needs another six
10
months or a year, or something like that, before
11
they're ready to submit their pediatric
12
supplemental application.
13
It may
It may also be depending on what the agency
14
decides about the safety and efficacy data of the
15
product in adults that, as in this case, the agency
16
may decide -- and individual divisions at the
17
agency have discretion to decide this -- to defer
18
pediatric studies until let's say long-term safety
19
data is collected in adults.
20
Again, in the approval letter for let's say
21
the adult indication, it specified the time period
22
very often as to when pediatric studies will begin.
A Matter of Record (301) 890-4188
110
1 2 3
DR. DRAKE: clarification.
I think that was an important
Thank you.
DR. MARCUS:
I perhaps can be a little more
4
direct in my comments as they relate to my initial
5
comments about historical perspective.
6
committee going down the secukinumab as a
7
comparator road.
8 9
I feel the
When I provided historical perspective, I tried to pull in non-dermatologic products just to,
10
hopefully, make the point that the risk-benefit
11
assessment for pediatric drug development for any
12
product, I think, is specific or should be specific
13
to the disease, the treatment, and how it relates
14
to the pediatric population.
15
I believe that one of the reasons that we're
16
here today to discuss atopic dermatitis is that
17
perhaps collectively, we've gotten locked into the
18
psoriasis pathway of pediatric drug development in
19
terms of assessing the need -- comparing products
20
developed for pediatric dermatologic indications to
21
the psoriasis paradigm, which I really would really
22
like to discourage because I think that we need to
A Matter of Record (301) 890-4188
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1
really make considerations for atopic dermatitis as
2
it occurs in pediatrics and for the products that
3
are under development or that are being recommended
4
currently off-label for use in atopic dermatitis.
5
I can say more but hopefully, I've made my point.
6
DR. DRAKE:
Dr. Beitz?
7
DR. BEITZ:
Yes.
I just wanted to say,
8
going back to the industry slide 30, how
9
provocative their proposal really is if deferral
10
for age 2 to 12 could be as early -- or late,
11
depending on your point of view -- as end of
12
phase 2 drug development for the adults.
13
a proposal for us to consider, I think that's very
14
provocative, considering what examples we have
15
provided to you today. DR. DRAKE:
16
I heard that, too.
If that's
When he said
17
end of phase 2, I thought that's pretty quick.
I'm
18
glad they're coming forward with these questions
19
because they're important.
20
offering any comments but I did think after phase 2
21
is pretty early to reduce the age down to that
22
level.
I probably shouldn't be
I mean that's just my personal comment on
A Matter of Record (301) 890-4188
112
1
it.
2
DR. BEITZ:
Right.
There may be --
3
DR. DRAKE:
The chair doesn't carry any
4
extra weight on this committee.
5
that with you all.
6
DR. BEITZ:
7
There may be specific
circumstances where that may be acceptable. DR. DRAKE:
8 9
I'm just sharing
In all fairness, yes, there may
be certain circumstances where it may be exceptions
10
but it is a little bit -- I think the important
11
point you brought up was the timing.
12
timing appropriate?
And thank you because that's
13
the important part.
I'm glad you put a number out
14
there.
15
move it -- we can adjust it, but I thank you for
16
putting forth a number.
17
point.
When is the
Phase 2 is a good number for us -- we can
That was a very important
18
Now, let's see.
I've got Dr. Siegfried,
19
Dr. Cohen, and Dr. Katz again.
20
DR. SIEGFRIED:
Dr. Siegfried.
I have a
21
couple of comments on things that were already
22
discussed.
One is the hesitancy of parents to put
A Matter of Record (301) 890-4188
113
1
children in clinical trials, and I think that
2
that's really a big misconception.
3
If we don't have clinical trials, then all
4
children are guinea pigs essentially because we're
5
treating them with no data.
6
parents of my patients at least would be very
7
willing to be in trials as opposed to just sort of
8
getting a drug that we know much less about.
9
And I think many, many
The other thing I wanted to just mention
10
about slide 21, because the emphasis is always put,
11
of course, on safety, and that's understood and
12
very important.
13
comparison to that, especially with regards to the
14
developing immune system, children who have atopic
15
dermatitis have obvious immune system
16
abnormalities.
But one of the things in
17
That's why they have atopic dermatitis.
18
There's a debate, of course, about whether it's
19
their skin barrier, whether it's immune function
20
but they certainly do happen together.
21 22
Hesitancy to study children early who have immune system abnormalities, we miss the
A Matter of Record (301) 890-4188
114
1
opportunity to study early intervention on their
2
immune system.
3
their immune system; it's that we're missing the
4
opportunity to correct an abnormality, and I think
5
that that's important point. DR. DRAKE:
6 7 8 9
So it's not that it's a risk to
point.
I think that is an important
Dr. Cohen? DR. COHEN:
Just to not beat a dead horse
but again, for us are really two issues:
one is
10
the efficacy and one is safety.
11
often look to the adult trials first, and then kind
12
of move it to the underage groups.
13
For new agents, we
But there's a lot of data that is either
14
unreported or not reported effectively that I think
15
I use -- and I know many of my pediatric
16
dermatology colleagues use when making a decision
17
about using a drug off-label.
18
data has been generated by our colleagues in other
19
pediatric subspecialties.
20
And most of that
So the pediatric gastroenterologist, the
21
pediatric rheumatologist, and the pediatric
22
oncologist have a ton of data out there on many of
A Matter of Record (301) 890-4188
115
1
the drugs that are recommended or as consideration
2
for alternatives for the pediatric age group.
3
Again, I use that, and my first concern
4
being that of safety.
5
their experience when making a decision about
6
whether or not to use a drug off-label.
7
I often use those data from
In terms of efficacy, that's kind of like
8
where we're out there a little bit on a limb.
But
9
again, my first concern is safety, and there's no
10
reason why we can't look at the data on many of
11
these drugs.
12
different but the drugs that are out there, we can
13
look at that.
14
And the newer drugs are a little
DR. DRAKE:
I want to follow up with a
15
question to you.
16
talked about decreased growth -- off the scale, not
17
on the appropriate scale for growth development and
18
whatnot in some of these kids that have had these
19
early drugs, right?
20
DR. COHEN:
One of your earlier comments, you
Well, no, actually, my concern
21
is that you just weigh the risk-benefit of this
22
against the risk-benefit of poor growth in children
A Matter of Record (301) 890-4188
116
1
with severe eczema, because we have children with
2
severe eczema who don't grow and develop normally.
3
DR. DRAKE:
That was going to be my
4
question.
5
misunderstood.
6
poor growth and stuff the drug but you contribute
7
it to the disease itself, which was my point I
8
wanted to make.
9 10
I'm glad I asked you because I think I I thought you were attributing the
DR. COHEN:
No.
Exactly.
That's the
balance.
11
DR. DRAKE:
Fantastic.
12
DR. COHEN:
I mean I think people are
13
worried about the potential toxicity and issues in
14
terms of growth and development.
15
with the worst disease, they're not growing and
16
developing normally to begin with.
But in these kids
17
DR. DRAKE:
That problem is preexisting.
If
18
they get a drug that is --
19
DR. COHEN:
It's effective.
20
DR. DRAKE:
-- theoretically is safe enough
21
to be acceptable, it might eliminate this other bad
22
problem of inadequate growth and development,
A Matter of Record (301) 890-4188
117
1
right?
2
DR. COHEN:
Absolutely.
3
DR. DRAKE:
Important point.
4
DR. COHEN:
It's just important to watch
5
those parameters.
6
them off-label even if we use data from pediatric
7
GI, rheumatology, and oncology.
8
very helpful. DR. DRAKE:
9 10 11
ma'am.
When we introduce drugs, we use
But that data is
That's an important point.
Yes,
You had a question. DR. CANTATORE-FRANCIS:
I just have a
12
comment.
13
dealing with a large population of children
14
affected.
15
or we are considering systemic medicines, all
16
dermatologists are not as comfortable with treating
17
children as pediatric dermatologists.
18
Thinking about this, practically, we're
When they are so severe that they need
Even now when you think about the wait time
19
sometimes for referrals to pediatric
20
dermatologists, which can be 3 months, 6 months
21
just to be with someone who might be comfortable or
22
"comfortable" prescribing one of the systemic
A Matter of Record (301) 890-4188
118
1
agents in an off-label manner, the time that goes
2
by that so many of these children are not being
3
adequately treated, and tends to be in that 2 to
4
12-year age group where parents and children are
5
suffering within that time.
6
It's just so important to be able to have
7
something that even a general dermatologist can say
8
this was approved on-label, they can get support
9
from the pharmaceutical companies, both financially
10
and parental support outside of the medical
11
community to help administer these medicines; and
12
just have that so the parents don't feel like
13
they're going out on a limb treating their
14
patients.
15
community across the country.
16
There is support amongst the medical
DR. DRAKE:
You've just said something very
17
important.
18
address reimbursement issues at all with this
19
committee.
20
shouldn't even mention it but I'm going to anyway.
21 22
By the way, we are not supposed to
That's not our job nor our task, and we
The reason why I'm going to mention it is because it also impacts what we can prescribe or
A Matter of Record (301) 890-4188
119
1
what can be prescribed sometimes for children.
2
Whether it's approved or not, in this era of the
3
ACA, the notion of a drug being approved is
4
becoming far more important than it used to be, it
5
seems to me.
6
Now, I may have a different perspective
7
because I practice at Massachusetts, but I think
8
it's becoming more and more important because
9
sometimes the third party payers are refusing to
10
cover anything unless it is FDA-approved i.e., the
11
FDA has taken a far more prominent role under the
12
ACA than ever before.
13
I mean I think you guys are -- the
14
activities of the FDA become more and more
15
prominent as time goes by.
16
wrongfully, that's the practical reality of the
17
situation today.
18 19 20
Rightfully or
I think Dr. Katz, you had your hand up. Dr. Green, I want to talk to you in just a minute. DR. KATZ:
Ken Katz.
I wanted to go back to
21
a comment that Dr. Maloney made earlier, which is
22
that all of us are uncomfortable testing drugs in
A Matter of Record (301) 890-4188
120
1
kids.
2
wonder if we should be more uncomfortable not
3
testing drugs in kids if -- the same kids who might
4
be in that trial who might be at risk in that trial
5
are the same kids who are going to be prescribed
6
medicines that we don't know how to dose, we don't
7
know whether they're safe, we don't know whether
8
they're effective or how long to use them for.
9
I think that's totally correct.
I just
So in the end, I think those kids, as
10
uncomfortable as I would be to study them, I'd be
11
probably more uncomfortable -- I think maybe we
12
should be more uncomfortable not studying them.
13
DR. DRAKE:
Dr. Green?
14
DR. GREEN:
They come along those lines.
15
You know, people are mentioning case reports a lot
16
and off-label use, but it's not so easy -- being in
17
the military, I can write things, and there's no
18
considerations for costs generally.
19
be but I don't have to worry about the person
20
getting it paid for.
21 22
There should
If there was a clinical trial of some sort, at least there's a mechanism to get the medicine.
A Matter of Record (301) 890-4188
121
1
If you're trying to ask an insurance company, Will
2
you support this off-label use of this medicine
3
that's not used in kids or for this condition, it's
4
going to be very difficult.
5
there's a trial somewhere, they can at least go to
6
that place and have a mechanism to get the medicine
7
and not pay an arm and a leg to get it.
8 9
DR. DRAKE: Other comments?
But at least, if
It's a form of access, yes.
Dr. Bergfeld?
10
there somebody else?
11
then Dr. Bergfeld.
12
too, right?
13
keep forgetting to look out.
14
I'm sorry.
I'm sorry.
Was
Dr. Kopelman and
And Dr. Raimer has her hand up,
Yes, Raimer.
Okay.
I'm sorry.
I
Lieutenant Commander, would you just smack
15
me upside the head when I don't look over here at
16
my list to see who to call on next?
17
late in the day.
18
DR. KOPELMAN:
19
DR. DRAKE:
It's getting
Loretta Kopelman.
She just said she won't slap me
20
upside the head.
She'll nudge me gently, but I
21
just need to remember to look over because I want
22
to be fair and keep things in order.
A Matter of Record (301) 890-4188
Yes.
122
DR. KOPELMAN:
1
I have a question about
2
slide 17, and you have the systemic agents listed
3
with the adverse effects, and some of them are
4
pretty grim.
Are any of them irreversible?
DR. GIANELLA-BORRADORI:
5
Most of these are
6
reversible.
Methotrexate, as we know, has been
7
used for about 30 years in the treatment of
8
children with acute lymphoblastic leukemia.
9
children receive -- they take it for about two
These
10
years on a weekly dosage.
And once they stop, most
11
of them recover fairly nicely.
12
be watched carefully but I think most hematologists
13
oncologists know how to deal with that well.
The delivery has to
14
Cyclosporine has been used in thousands of
15
children following allograft, both organ allograft
16
and bone allografts.
17
malignancy.
18
them are reversible.
We know there's some
We know all the side effects.
Most of
Kidney can remain damaged for quite a long
19 20
time.
Sometimes it's difficult especially in the
21
transplant setting to know whether it's a
22
transplant or it's the drug.
A Matter of Record (301) 890-4188
123
1
Azathioprine also recovers.
Basically, it
2
kills lymphocytes and modulates the immune system.
3
MMF, most of these recover.
4
malignancy occurs, then obviously the malignancy
5
becomes a problem.
Obviously, once the
6
But the side effects, the malignancy
7
independent, they all recover with the exception of
8
nephrotoxicity or changes in kidney, which can
9
persist into adulthood.
10
Does that answer your
question?
11
DR. DRAKE:
Dr. Bergfeld, and then Raimer.
12
DR. BERGFELD:
I'll be brief.
Dr. Bergfeld.
13
I just wanted to add to the list of safety
14
precautions.
15
important but so is reproductive in this age group.
I think growth and development are
16
DR. DRAKE:
Okay.
17
DR. RAIMER:
Dr. Raimer, Sharon.
I'm just going to kind of
18
restate what I think I've heard.
19
recognize that there are children who are suffering
20
and need better drugs, and none of us want to put
21
children at risk in studies.
22
I think all of us
So we can't have it both ways.
A Matter of Record (301) 890-4188
If we agree
124
1
that children are going to need to be studied, I
2
think we need to look at, okay, at what point in
3
time -- I think this has been brought up.
4
what point in time are we going to study them?
5
we going to study adults first?
6
study adults and adolescents first?
7
But at Are
Are we going to
Then at what point in time are we going to
8
start to study the younger children?
9
think it needs to be done.
Because I
It's just hard for us
10
to say, Let's do it, when we're worried about not
11
wanting to cause harm to any child.
12
DR. DRAKE:
Dr. Corcoran?
13
DR. CORCORAN:
I just wanted to add on
14
additional thought about slide number 17.
15
know, if you think about it, at some point, if you
16
look at all those things, and certainly many of
17
them are bad things.
18
the benefit risk profile moves toward benefit.
19
You
In the right circumstances,
That has come over a long period of time in
20
which we know more about the drugs, and so we got
21
to really -- I think to go to the earlier comment
22
about at what point do we know enough to be able to
A Matter of Record (301) 890-4188
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1
make sure that there's sufficient benefit to be
2
able to start studying it.
3
is we need to know enough information to be able to
4
know when to get started, and I think that's where
5
we need to look at.
6
I think the whole idea
As much as we'd love to have drugs on the
7
market where there are no side effects -- I've yet
8
to work on one of those.
9
they do have side effects, certainly have great
And yet the ones, even if
10
benefit for the patients that take them.
11
think it's a matter of really looking at it and
12
trying to figure out when the right point is to
13
start to generate more information on children.
14
So I
For these children that have a bad disease,
15
it may be sooner rather than later.
16
do we actually say this is soon enough?
17
I think about the examples that have been brought
18
up, if you really follow that model, you will start
19
to only generate data on these children years after
20
you get it on to market.
21 22
At what point Because if
So we're kind of playing around with drugs that are on the market being used by
A Matter of Record (301) 890-4188
126
1
well-intentioned people that really are basing it
2
on no data.
3
to generating more data on children sooner rather
4
than later.
5
always be chasing our tail with bad diseases.
So I think we really do need to move
We have to.
DR. DRAKE:
6
Otherwise, we're going to
What I'm beginning to
7
hear -- Dr. Williams, I think you're next.
8
going to call you in a sec.
9
hear is that we must be careful.
I'm
What I'm beginning to In our zeal to
10
protect these children, are we going to protect
11
them to death?
12
something that could really be beneficial?
Are we going to protect them out of
The second thing is there's nobody who gets
13 14
more carefully-monitored than patients in studies.
15
Clinical studies are -- I mean if you're just
16
treating a patient and they're not in a clinical
17
study, you may see them back in several months or
18
whenever you can if they can't get in. If they're in a study, you have a
19 20
regular -- you see them regularly, you monitor them
21
carefully, you can identify potential side effects
22
early.
So am I hearing that correctly that this
A Matter of Record (301) 890-4188
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1
may be a better time to look at them early on in
2
the process so that we know what's going on?
3
Dr. Williams, I'm going to call you.
4
You
have a comment on that, Dr. Cohen? DR. COHEN:
5
Go back to slide 17.
Those were
6
drugs.
There was a ton of data on safety and
7
children.
8
low-hanging fruit.
9
DR. DRAKE:
Yes.
10
DR. COHEN:
And we can pluck that fruit
It's out there already.
It's
11
right away because again, our number 1 concern is
12
safety.
13
two decades, and many of us are using them off-
14
label now.
15
buddies in other pediatric specialties, and we can
16
collect that data today.
17
story.
But those drugs have been used for
But we can go back and talk to our
New drugs, different
These drugs, old fruit.
18
DR. DRAKE:
Dr. Williams?
19
DR. MYRIE-WILLIAMS:
I just had question.
20
Those young children who are so severely, severely
21
affected, and some of the adults who retained the
22
same degree of involvement, do many of those
A Matter of Record (301) 890-4188
128
1 2
patients have elevated IgE? Because some of the little ones do, and some
3
of the adult ones I've seen have.
4
any kind of role in how you would think about their
5
treatment and what might work better for the ones
6
who really have elevated IgE?
7 8 9
DR. DRAKE:
Would that play
Dr. Siegfried, do you want to
answer that? DR. SIEGFRIED:
Eighty percent have overly
10
elevated IgE.
11
phenotype.
12
the things that we've discussed here around the
13
table, I think including the drugs that are
14
available now with the list of very scary side
15
effects, although we all use them.
16
use them especially in other subspecialties with a
17
high degree of comfort but we don't have as much
18
data as we'd like.
19
And atopic dermatitis is a
There's probably many subsets but all
And many of us
But it speaks to having comparator studies
20
as opposed to placebo-controlled studies because
21
we've discussed the problem with placebo risks.
22
And there are many, many issues related to protocol
A Matter of Record (301) 890-4188
129
1
design, but it speaks to the importance and the
2
real great opportunity to have a guidance document
3
in going forward for this because I think it would
4
really, really help incentivize great studies that
5
we can all be comfortable with. DR. DRAKE:
6
You know what I'm going to do
7
right now, and I apologize.
Keep your questions
8
those of you who are raising your hands.
9
questions.
Keep your
I want to ask Dr. Cline to do her
10
presentation.
I don't want to get behind schedule.
11
Do you mind?
12
that was supposed to be at 3 and we're a few
13
minutes late so I don't want to get behind.
14
one thing that's important is I want to make sure
15
that we're on time for the public hearing.
Let's do that.
Let's do that because
The
Please go ahead, and then that way, we're
16 17
right on target for the open public hearing at
18
3:30.
19
have other questions, be sure your name is on her
20
list.
21 22
And we'll keep the list running.
If you
FDA Presentation – Michelle Roth-Cline DR. ROTH-CLINE:
My name is Michelle
A Matter of Record (301) 890-4188
130
1
Roth-Cline.
2
the agency as I mentioned.
3
agency is really a sort of ethics consultant in the
4
same way as the sort of ethics consultation service
5
within a hospital where different review divisions
6
can request our input in expertise for a variety of
7
considerations.
8 9
I work as a pediatric ethicist here in My role within the
So I think consistent with a lot of what I've been hearing the committee say already, I
10
think that in pediatrics, we've really moved from a
11
view that we must protect children from research to
12
a view that we must protect children through
13
research.
14
The reason why is because we're trying to
15
prevent these N of 1 studies every time a child
16
comes in to the office, and we don't know what the
17
right dose is.
18
information is to really be able to collect that
19
systematically.
20
to support the safe and effective use of drugs and
21
biological products.
22
We don't know what the safety
Protecting children requires data
There are four principles that I think
A Matter of Record (301) 890-4188
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1
underlie the basic ethical framework in pediatrics.
2
And I will say I think there's agreement on these
3
internationally, although I'll speak today specific
4
to the U.S. Regulatory framework, that is children
5
should only be enrolled if a scientific and/or
6
public health objective cannot be met by enrolling
7
adults, that is subjects who can consent for
8
themselves.
9
If there's no direct therapeutic benefit to
10
the children, the risks to which the children ought
11
to be exposed should be low.
12
be placed at a disadvantage by being enrolled in a
13
clinical trial, and vulnerable populations should
14
have a proxy to consent for them if they're unable
15
to consent for themselves.
16
Children ought not to
So from principles 2 and 3 in this last
17
slide, the additional safeguards for children that
18
are in FDA regulations really codify, I think,
19
these ethical principles.
20
children under FDA regulations either must be
21
restricted to these lower risk categories of
22
minimal risk or a minor increase over minimal risk,
So research involving
A Matter of Record (301) 890-4188
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1
or must present risks that are justified by the
2
anticipated direct benefits to the child, which are
3
also reasonable relative to any available
4
alternative treatments.
5
So we think of these -- another way to think
6
of these things is the sort of lower risk and
7
higher risk pathway.
8
disagreement today that systemic agents for atopic
9
dermatitis can all have serious risks.
I think that there's no
And so, I'm
10
going to be talking exclusively today about the
11
higher risk pathway.
12
So this is found in FDA regulations.
And
13
you can see the citation here, but I wanted to
14
present to you the sort of original language that
15
is in the regulations.
16
It says, "Clinical investigations that
17
present the prospect of direct benefit may be
18
approvable if the risk is justified by the
19
anticipated benefit to the subject, the relation of
20
the anticipated benefit to the risk is at least as
21
favorable as that presented by available
22
alternative approaches," and as well there are
A Matter of Record (301) 890-4188
133
1
requirements about consent and permission that I'm
2
not going to go into today.
3
So the framers of our regulations, when
4
these regulations were being codified in the late
5
'70s, really modeled this category on clinical
6
decision-making.
7
discussions of the National Commission, it was
8
really talking about, well, would a reasonable
9
clinician, given the available alternatives and the
If you go back to some of the
10
severity of the disease, consider this
11
investigational agent, let's say, for the treatment
12
of this disease as a reasonable therapeutic option.
13
Now, the willingness of a clinician to give
14
a product doesn't per se indicate anything about
15
whether the product may be effective.
16
certainly patients that have refractory diseases,
17
clinicians are often willing to try a lot of
18
different things for which there isn't a great
19
evidence base.
20
But
So here's a point about the timing of
21
pediatric studies.
And I will say that although
22
practice varies across the agency, I think the goal
A Matter of Record (301) 890-4188
134
1
of the agency as a whole, when a product is being
2
developed for both adult and pediatric indications,
3
ought to be concurrent licensure.
4
recent years, a number of legislative efforts that
5
have sort of moved us along that particular
6
pathway.
We've had, in
But as was alluded to, there is sequential
7 8
development.
And there may be parallel development
9
with adult studies, really, depending on the
10
product.
And it is a very much a product-specific
11
decision, and a product-specific discussion within
12
the agency when we think about these things. From an ethical standpoint, we're actually
13 14
often asked the question of when ought we begin
15
studies in pediatrics and when is the appropriate
16
time.
17
Pediatric studies should be initiated as soon as
18
sufficient information is available to meet the
19
ethical and regulatory requirements under the
20
higher risk pathway, that is, the risk to the
21
patient is justified by the anticipated benefit and
22
that risk-benefit is reasonable in relation to the
The sort of simple answer is this.
A Matter of Record (301) 890-4188
135
1
available alternatives.
2
has been met, then pediatric studies ought to
3
begin.
4
We say once that burden
Now, clearly, there can be a lot of
5
discussion and debate about when specifically for
6
any given product that burden has been met, but
7
from a sort of high-level perspective, that's where
8
we begin.
9
From a policy standpoint, if we look at our
10
two policy choices, we can either say, well, a
11
child in a study population may be a treated with a
12
particular new therapeutic agent for atopic
13
dermatitis, in this case, because the balance of
14
risks and benefits of that agent appears to be at
15
least as favorable to that child as other systemic
16
agents, or we can make a different policy decision,
17
and we can say we should obtain more information
18
regarding the risks and benefits of the new agent
19
in adults, because we do not yet have sufficient
20
information to conclude that the balance of risks
21
and benefits of the new agent may be considered
22
similar to other systemic agents.
A Matter of Record (301) 890-4188
136
1
But I want to point out that we're not -- by
2
not studying new agents in children, we're not
3
saving these children from risks; that is we may be
4
saving them from the risks of that particular new
5
systemic investigational agent.
6
heard, these same children are going to be treated
7
with other systemic agents that have a pretty
8
harrowing list of risks that we just talked about
9
earlier.
10 11
But as we've
So I think that that's really important
to understand and keep in mind. So clearly, there is room for disagreement
12
about the timing of pediatric studies, and I
13
think -- here are just a few of the considerations
14
that come into play:
15
the disease and the impact on the health and
16
quality of life; that is the probability in
17
magnitude of the harm and potential benefits from
18
the drug versus potential alternative agents; and
19
as well, the degree of tolerable uncertainty about
20
the probability of harm given the known risks of
21
the disease and the known risks of other agents.
22
that is the seriousness of
I think it's also very important to keep in
A Matter of Record (301) 890-4188
137
1
mind the broader context when we're talking about
2
the timing of pediatric studies, and that is when
3
the drug is likely to be marketed for any
4
indication, not just atopic dermatitis.
5
To pick on dupilumab again, not only were
6
the phase 2 data from dupilumab and atopic
7
dermatitis recently published in the New England
8
Journal, but the phase 2 data from asthma in adults
9
as well was recently published in the New England
10
Journal.
11
than one indication and may be approved for
12
indication sooner than others.
13
So clearly, drugs may be studied for more
I think it's also important to understand
14
that patients, clinicians, and regulatory agencies
15
all have to ask themselves these risk-benefit
16
questions about when is the right time to start
17
these agents.
18
answers.
19
We may come up with different
I won't go into the study population, but I
20
did want to point out that I think that we're
21
talking about children today really who do have
22
severe disease.
These slides have been shown a
A Matter of Record (301) 890-4188
138
1
couple of times already.
2
But I want to finish with some lessons from
3
past products that I've learned I think from having
4
been around the agency for a while in pediatrics.
5
And that is if a product is marketed in adults and
6
represents a meaningful therapeutic benefit, at
7
least some patients and clinicians may be willing
8
to accept the risk and use the product in children
9
when we don't have good data, off-label, when we
10
don't have information about dosing and safety and
11
so on.
12
If off-label use becomes common, it has, in
13
other product development areas, become impossible
14
to do randomized, controlled trials at all of those
15
agents in children because clinicians and patients
16
aren't willing to participate.
17
From an ethical standpoint, we may say,
18
well, we don't have evidence about it, and so it
19
wouldn't be unethical to do a trial.
20
and clinicians feel differently, and they won't be
21
a part of the trial, and they won't enroll.
22
So there is a window of opportunity
A Matter of Record (301) 890-4188
But patients
139
1
sometimes for pediatric trials if we're serious
2
about getting the data we don't want to miss.
3
It has also been true that products have
4
become standard of care in pediatrics absent
5
information about the risks and benefits in
6
children with that particular disease.
7 8
So thank you, and I'm happy to try to answer any questions. Clarifying Questions
9 10
DR. DRAKE:
I'm going to do something here,
11
and I apologize.
12
because we got a little behind.
13
do is get our -- because I'm serious about making
14
sure the open public hearing is on time.
15
And doctor, I owe you an apology But what I want to
So can you guys live with a 5-minute break
16
if we do 5 minutes for questions and then a
17
5-minute break to get to the restrooms and come
18
back here at 3:30?
19
Okay.
Well, 5 minutes for questions.
Then
20
we can ask her more questions during the
21
discussion.
22
of questions, and then we're going to take a quick
So we're going to do 5 minutes' worth
A Matter of Record (301) 890-4188
140
1
5-minute break.
Lieutenant Commander, are we handling this
2 3
okay?
4
Who's next?
5
Then we'll hit the open hearing.
All right.
We're good to go.
All right.
Dr. Maloney?
DR. MALONEY:
So the "therefore" on your
6
last slide is that, therefore, we need to start
7
studies early and not wait late.
8
"therefore?"
9
"therefore --"
Is that your
You got three good points, and
10
DR. ROTH-CLINE:
11
DR. MALONEY:
12
DR. ROTH-CLINE:
Yes.
Okay.
You left that one off.
But the question is how
13
early or how late, depending -- and I think that's
14
really the question that we're here to ask the
15
advisory committee.
16
not be early to you, and what's late to me may not
17
be late to you.
18 19
DR. DRAKE:
Because what's early to me may
Is phase 2 early or late to you?
Let me ask --
20
DR. ROTH-CLINE:
21
DR. DRAKE:
22
I'm sorry?
After phase 2, is that early or
late from your point of view?
A Matter of Record (301) 890-4188
141
DR. ROTH-CLINE:
1
So it depends on the
2
product.
We have often started -- when we
3
proceeded from, let's say, adult development to
4
pediatric development, we've often said that
5
there's preliminary safety and proof of concept
6
information in adults at the end of phase 2; that
7
is we don't need efficacy in adults necessarily. There are some times when we do but,
8 9
generally speaking, when we have the sort of proof
10
concept around potential benefit and safety can be
11
at the end of phase 2.
12
what population of children do you study, number
13
one, and what age group of children do you study?
But the question is then
The ethical requirements under subpart D
14 15
don't vary whether you're a neonate or a 17-year-
16
old.
17
so forth, matter greatly as well as endpoint
18
development.
19
But scientific considerations, and so on and
Clearly in children who are nonverbal, you
20
may need different endpoints than you do in adults.
21
And so there's scientific and practical
22
considerations that can dictate when pediatric
A Matter of Record (301) 890-4188
142
1
studies should be performed.
2
on the agent, and it depends on the safety and
3
efficacy profile of particular agents. DR. DRAKE:
4
Okay.
But again, it depends
Between now and break
5
stands, Dr. Horii, Dr. DiGiovanna and Dr. Gaspari.
6
Three questions. DR. HORII:
7
Hi.
This is Kim Horii.
This is
8
more of a comment than a question.
I think we've
9
been discussing quite a bit about timing of when
10
you would want to start these trials after phase 2
11
or phase 3.
12
know they had in some of those prior slides about
13
age.
But no one has really brought up -- I
14
If it's over 12, then we will consider but
15
atopic dermatitis is a disease of oftentimes young
16
childhood.
17
significant effects in their school life, quality
18
of life.
19
kids, appropriately after age 12, they may have
20
already had significant damage at that point.
21 22
These kids are going through
And if you wait to actually study these
So again, I don't know if there's an ideal but thinking about in clinical trials where they're
A Matter of Record (301) 890-4188
143
1
going to be monitored closely allowing younger
2
children to also be evaluated.
3
Because my concern is if it's approved or
4
looked at safely in kids that are 12, then there
5
will be a lot of off-label use in younger children,
6
and younger children, 2-, 3-, 4-, 6 year olds may
7
have different drug metabolism than 12 year olds.
8
So I think the age of the children needs to be
9
considered as well in our discussions.
10
DR. DiGIOVANNA:
John DiGiovanna.
As part
11
of this discussion, there has been a number of
12
comments about risk-benefit ratio, and the obvious
13
thing people think of is that that refers to the
14
patient.
15
But the risk that's motivating us may be the
16
risk to the physician or even the risk to the
17
regulator as far as doing something now versus
18
putting it off.
19
I think part of the balance should be, when
20
you're talking about efficacy versus toxicity, it's
21
not only the drug toxicity, although it has been
22
mentioned before, it's actually the disease
A Matter of Record (301) 890-4188
144
1
toxicity that we're putting off. I think the problem here is that we really
2 3
don't have good metrics.
For adults, for example,
4
with psoriasis, people can talk about days out of
5
work or missed work.
6
very much as far as quantifying what actually
7
happens during a pediatric age with respect to
8
being out of school, the social issues that result,
9
the failure to perform in school, and really the
10
lifelong cost of having a chronic illness that's
11
not addressed.
But I really have not seen
I think it would help if that was considered
12 13
part of the equation.
14
encourage what you're suggesting, is that if you
15
lose the window of timing opportunity, it just
16
becomes easier to push it down the road from the
17
perspective, not so much of the patients' but of
18
those of us who are doing the pushing-down-the-
19
road.
20
DR. ROTH-CLINE:
And I think it would help
I think from a regulatory
21
perspective or from the perspective of subpart D,
22
the risks and benefits are really intended to speak
A Matter of Record (301) 890-4188
145
1
directly to the individual patient.
2
risks and prospect of direct benefit to each
3
individual child who is enrolled.
4
So that is the
But I absolutely agree with you, with your
5
comment, that there is an important component,
6
which is the risks of the disease, the risk of the
7
disease being untreated, and that sort of thing,
8
that really does enter in an important way to these
9
determinations.
10
DR. DRAKE:
Dr. Gaspari, last question.
11
We'll break, and then we'll put Ms. Boyce on the
12
line for right after break.
13
DR. GASPARI:
The only thing I wanted to add
14
is about protecting children from risks from the
15
standard of care.
16
discussion about the use of corticosteroids, and
17
really healthcare providers' overreliance on both
18
topical and systemic corticosteroids, and so try,
19
and kind of another justification.
20
I think we had some early
Of course, we're comfortable.
We know the
21
risks but we should become less comfortable with
22
the risks of corticosteroids and change the
A Matter of Record (301) 890-4188
146
1
paradigm.
And it would be another reason so
2
justify clinical trials in small children. There's a need to move beyond topical
3 4
steroids and keep that in the tool box, either
5
alone or in combination but less in the reliance.
6
So like on page 11, under definitions, I would put
7
corticosteroid dependence as another part of the
8
definition. Or page 17, systemic agents, are we going to
9 10
include corticosteroids?
But all these systemic
11
agents come in after corticosteroids?
12
are on steroids a long time, we can't taper them
13
off, and they're steroid-dependent.
When kids
So I just wanted to add that about how we
14 15
become so dependent on corticosteroids, and we need
16
to find other alternatives in small children. DR. DRAKE:
17
All right.
Thank you, Tony.
18
It's a very good point.
19
way.
20
We're going to come back for open public hearing
21
and more discussion.
22
I agree with you by the
Let's have a 5-minute break, 5 minutes.
Thank you.
(Whereupon, a recess was taken.)
A Matter of Record (301) 890-4188
147
1 2
Open Public Hearing DR. DRAKE:
So here's the plan.
What we're
3
going to do right now is we're going to go to the
4
open panel discussion.
5
looking for my notes here.
6
All right.
7 8 9
And just a second, I'm
So let me start.
This is the
open public hearing session of the afternoon. Both the Food and Drug Administration and the public believe in a transparent process for
10
information-gathering and decision-making.
11
ensure such transparency at the open hearing
12
session of the advisory committee meeting, FDA
13
believes that it's important to understand the
14
context of an individual's presentation.
15
To
For this reason, the FDA encourages you, the
16
open public hearing speaker, at the beginning of
17
your written or oral statement to advise the
18
committee of any financial relationship that you
19
may have with the sponsor, its product, and if
20
known, its direct competitors.
21 22
For example, this financial information may include the sponsor's payment of your travel,
A Matter of Record (301) 890-4188
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1
lodging or other expenses in connection with your
2
attendance at the meeting.
3
encourages you at the beginning of your statement
4
to advise the committee if you do not have any such
5
financial relationships.
6
Likewise, FDA
If you choose not to address this issue of
7
financial relationships at the beginning of your
8
statement, it will not preclude you from speaking.
9
The FDA and this committee place great importance
10
in the open public hearing process.
11
and comments provided can help the agency and this
12
committee in their consideration of the issues
13
before them.
14
The insights
That said, in many instances and for many
15
topics, there will be a variety of opinions.
16
of our goals today is for this open public hearing
17
to be conducted in a fair and open way and where
18
every participant is listened to carefully and
19
treated with dignity, courtesy, and respect.
20
Therefore, please speak only when recognized by the
21
chairperson.
22
One
Thank you for your cooperation.
So now, will speaker number 1 please step to
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1
the microphone?
2
yourself.
3
you're representing for the record.
4
Identify yourself and introduce
State your name and your organization
DR. DAYHOFF-BRANNIGAN:
Thank you.
Hi, my name is
5
Dr. Margaret Dayhoff-Brannigan, and I am a senior
6
fellow at the National Center for Health Research.
7
Our research center scrutinizes scientific and
8
medical data and provides objective health
9
information to patients, providers and
10 11
policymakers. We do not accept funding from pharmaceutical
12
companies, and I therefore have no conflicts of
13
interest.
14
here today.
Thank you for the opportunity to speak
15
I completed my Ph.D. in biochemistry and
16
molecular biology at the Johns Hopkins School of
17
Public Health.
18
diagnosed with moderate atopic dermatitis.
19
the perspectives of both a researcher and parent
20
here today.
21 22
In addition, my 2-year-old has been I bring
My child started to have eczema on his face, scalp, chest, and back before he was 3 months old.
A Matter of Record (301) 890-4188
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1
It took months of new lotions, bath soaps,
2
detergent, diet changes, allergy testing, and
3
prescription topicals, corticosteroids, to finally
4
get his eczema under control. I'm very thankful we were able to treat him,
5 6
but I understand the impact this disease has on
7
patients with an unmet need.
8
critical to ensure that proper clinical testing is
9
done on all age groups before subjecting pediatric
10
patients to treatment options that may not be safe
11
or effective for children their age.
However, it's
Eczema in children under the age of 2 is a
12 13
very different disease than in older children and
14
adults.
15
body and is often found on the chest, back, and
16
face.
17
food allergies.
18
inappropriate to extrapolate results from adult
19
clinical trials to this age group.
20
It covers a much larger portion of the
Eczema in this age group is often related to For these reasons, it's
In fact, sub-group analyses are important
21
for all children.
Metabolism rates change
22
considerably during childhood, so it's important to
A Matter of Record (301) 890-4188
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1
have clinical trials that analyze dosages for
2
different age groups and weights.
3
Pediatric patients with eczema are at a
4
higher risk for allergic reactions to any exposure,
5
which puts them at risk when trying new treatments.
6
This elevated risk should be weighed when
7
considering the risk-benefit analysis for any
8
treatment.
9
The bottom line is that pediatric patients
10
with severe disease that does not respond to
11
topical corticosteroids might appropriately be
12
enrolled in a clinical trial for an experimental
13
treatment, whether a new drug or a current therapy
14
that has inadequate testing.
15
should not be open to pediatric patients that have
16
not exhausted safer options, such as lifestyle
17
changes and topical corticosteroids.
18
But these trials
We ask you to be cautious as you consider
19
systemic treatments for atopic dermatitis in
20
pediatric patients.
21
non-life-threatening, so while it severely impacts
22
quality of life, children should not be exposed to
Atopic dermatitis is
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1
a treatment that could cause any type of permanent
2
or substantial harm, however rare.
3
Considering the ethics, children are unable
4
to make informed decisions, but it's difficult to
5
put parents in that position with therapies that
6
have not been tested on large numbers of children
7
over a long period of time.
8 9
One major problem that's been discussed here today is that drugs are currently being used off-
10
label to treat atopic dermatitis systematically,
11
all carry boxed warnings about side effects and
12
risks, and the long-term effect of these treatments
13
is unknown.
14
Despite the black box warnings, these drugs
15
are being used in pediatric patients where there's
16
very little data on their safety and efficacy.
17
Patients in these situations would be better served
18
by participating in clinical trials where parents
19
are made aware of the risks, and patients are
20
carefully monitored by doctors who are
21
knowledgeable about the risks.
22
Under these careful conditions, children
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1
would be randomized to receive a novel treatment
2
using the standard of care as a control.
3
may feel desperate to try treatments for atopic
4
dermatitis for their children, but they may not
5
understand that previous research is often
6
inadequate to prove how safe or effective the new
7
treatment is for their children.
8 9
Parents
It is FDA's job to make sure that treatments are first proven to be safe and effective in animal
10
models for all ages.
There should also be safety
11
data from adults and older pediatric patients
12
before it's ethical to begin testing on children.
13
If a systemic treatment for atopic
14
dermatitis is approved by FDA, it is essential that
15
all labels should indicate safety and efficacy
16
information for each age group tested.
17
product has not been tested in a specific pediatric
18
population, the label should clearly state that.
19
If a
Atopic dermatitis affects a very young
20
patient population, so it's critical to have safety
21
information for all age groups to prevent dangerous
22
off-label use.
This is a vulnerable patient
A Matter of Record (301) 890-4188
154
1
population; the benefits for treatment must be
2
proven to outweigh the risks.
3
We urge the FDA not to just grant
4
pharmaceutical companies waivers for clinical
5
trials on pediatric patients.
6
public health advocate, and mother, I thank you for
7
your consideration of these important issues.
8
DR. DRAKE:
9
speaker number 2 present?
10
As a researcher,
Thank you very much.
DR. VLAHAKIS:
Would
Good afternoon, everyone.
My
11
name is Nick Vlahakis.
I'm a physician and a
12
medical director representing Roche-Genentech who
13
are developing a monoclonal antibody, lebrikizumab,
14
in moderate to severe atopic dermatitis currently
15
in adult patients.
16
Firstly, I wanted thank you for the
17
opportunity to speak at today's advisory committee.
18
And I'd also like to express our appreciation to
19
the FDA for convening this advisory committee to
20
consider such an important topic.
21 22
We identified some particular points in both the FDA and sponsor briefing materials that we'd
A Matter of Record (301) 890-4188
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1
like to emphasize our support for.
2
agree that based on the higher pediatric prevalence
3
compared to adults, the burden of disease, and the
4
limited therapeutic options that we would support
5
the fact that there is a high unmet medical need in
6
the pediatric AD patient population, who are
7
inadequately controlled by topical therapies.
8 9
Firstly, we
I think this sets the counterbalance to a very robust discussion already around the timing of
10
pediatric studies, and it struck me as I was
11
sitting in the audience that our Roche-Genentech
12
motto highlights this challenge, "Doing now what
13
patients need next."
14
As such, we believe flexibility should exist
15
to allow for the possibility of initiating
16
pediatric trials early in development under the
17
appropriate circumstances.
18
phase 2 studies of adolescents and adults with
19
atopic dermatitis might be considered for an
20
investigational medicine before completion of phase
21
3 trials in adults.
22
For example, concurrent
In particular, when these trials are being
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156
1
conducted in another relevant atopic disease, such
2
as asthma, and I think Dr. Cline and others had
3
made this point.
4
the earlier presentations is the importance of
5
defining the patients who are considered as
6
inadequately controlled by topical therapies.
7
A second point to highlight from
We believe the following statement from the
8
sponsor's briefing materials was of particular
9
importance in this matter, and I'll quote, "AD
10
requiring systemic treatment is not unresponsive to
11
high potency topical steroids, but the response is
12
not sufficient, or the side effects of the topical
13
drugs, especially the higher potency TCS, are not
14
tolerable in the long-term."
15
The key message we would like to highlight
16
from this statement is that the patients who
17
benefit from systemic treatments are not just
18
limited to those who demonstrate complete topical
19
therapy resistance.
20
This message is supported also by the table
21
that was presented in the briefing document, which
22
pointed out that clinicians continue to prescribe
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157
1
topical steroids in order to manage patient's
2
disease symptoms as pointed out, like pruritus,
3
whilst initiating that next step up therapy.
4
This step up therapy paradigm is also
5
reflected in other inflammatory clinical diseases
6
such as in asthma and rheumatoid arthritis and
7
their associated treatment guidelines.
8 9
Lastly, we'd like to raise a point for consideration by the advisory committee that was
10
already highlighted in previous presentations, and
11
that's around severity assessment measures for use
12
in clinical studies.
13
We'd like to advocate for a greater
14
alignment among stakeholders regarding the
15
appropriate assessment tools in order to
16
consistently and accurately define disease severity
17
and measure clinically meaningful treatment
18
response.
19
We'd like to encourage clinicians,
20
guideline-making bodies, regulatory agencies,
21
patient advocacy groups, and all sponsors to
22
collaborate on an international level toward the
A Matter of Record (301) 890-4188
158
1
goal of harmonizing these assessment tools for use
2
in clinical trials, in order to support consistency
3
and expediency in and among programs for the
4
growing number of AD targeted therapies.
5
Thank you very much for your consideration.
6
DR. DRAKE:
7
helpful.
Block.
Actually, that was
Next one, speaker 3.
MS. BLOCK:
8 9
Thank you.
Hi.
Good afternoon.
I'm Julie
I am the president and CEO of the National
10
Eczema Association, and I'm here to introduce our
11
speakers today, members of our National Eczema
12
Association.
13
interest, but they do have eczema [inaudible -off
14
mic].
15
And they have no conflicts of
GRACIE NYE:
Hi.
My name is Gracie Nye, and
16
I'm 17 years old, and I've suffered from severe
17
eczema my entire life.
18
the worst thing to endure, and I'm blessed by that,
19
but that doesn't mean it hasn't come with
20
obstacles.
21 22
I know that eczema is not
My eczema has kept me from doing many things as a child like sleepovers, summer camps and pool
A Matter of Record (301) 890-4188
159
1
parties because I was so self-conscious about my
2
body.
3
life, because it's the only thing that worked, but
4
it continues to cause damage to my skin.
I have used topical steroids for most of my
I have tried every systemic my doctor has
5 6
recommended including methotrexate and
7
cyclosporine, but nothing has worked.
8
dermatologist has mentioned systemic drugs to me
9
that would work, but I can't, because I'm not old
10
My
enough. I thought why isn't there any development in
11 12
drugs for children?
13
about what my life would be like if I didn’t have
14
eczema.
15
every night if I'll wake up in the morning with
16
claw marks that I had made from subconsciously
17
scratching in my sleep.
18
I spent a lot of time thinking
To think that I wouldn't have to wonder
To think that I could carelessly wear a
19
swimsuit and not worry about showing the stretch
20
marks on my legs from constant steroid use; to take
21
away the memories of missing out on Spirit Week at
22
my school because I couldn't move from my bed
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160
1
without experiencing sharp pains from all the
2
scratches all over my waist and arms.
3
Sometimes when my skin was really broken
4
down and I couldn't cover it with clothing, I would
5
lie to people and tell them that my dog had jumped
6
up and scratched me.
7
people that I was capable of doing this to myself.
8
I’d give almost anything not to lather myself in
9
Vaseline every night to the point where my pajamas
10 11
I couldn't bear to tell
were heavy with grease. This is all to say that I don't believe
12
eczema has ruined my life.
13
overcome immense adversity, embrace the idea of
14
inner beauty and love others well.
15
into the hospital to receive treatment because the
16
scratches on my body were starting to become
17
infected, and I wasn't able to move.
18
It has taught me to
Recently I went
I was so scared to come back to school and
19
be met with people asking me why I was in the
20
hospital and not know what to say.
21
worst parts of having eczema is that for the most
22
part I couldn't control it.
A Matter of Record (301) 890-4188
One of the
161
1
I want my skin to heal so badly, but I never
2
know that I'm hurting myself until the next morning
3
when it's too late.
4
I realize that a door will be open to me that
5
offers several options to cure my skin that I don't
6
have now.
7
sympathy for the little girl in the derm office
8
with red splotches and dry skin on her face, that
9
doesn't have any options to help her skin.
10
As I come close to turning 18,
But that doesn't mean I don't still have
She will muddle through as I did and carry
11
with her the same insecurities.
Children should be
12
the priority because they have their whole lives
13
ahead of them to struggle with eczema, whereas
14
adults have learned to deal with this disease over
15
their lifetime.
Thank you.
16
DR. DRAKE:
Thank you.
17
ISAIAH DIXON:
My name is Isaiah Dixon, and
18
I am 13 years old.
I really don't remember a time
19
when I didn't have eczema, because I had eczema
20
since I was three years old.
21
deal with every day.
22
different.
It is something I
Each day I feel something
Some days I feel tight, itchy, dry.
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1
Some days I am in severe pain because my
2
skin is red, raw, with open sores.
3
feel all these things together.
4
hospital four times because of my eczema.
5
longest time was for a week.
6
from home and a week from school.
7
Sometimes I
I have been in the The
That meant a week
It is very hard to stay tough living with
8
eczema for 10 years.
9
down crying to my parents, why I -- I mean I am
10
tired of eczema.
11
will God heal me?
12
Lately, I have been breaking
And I often think to myself, when
I wish I was like my brother and sister who
13
do not have eczema.
Eczema keeps me from doing the
14
things that I enjoy the most, like going to the
15
beach, riding my bike, or going for a walk, and
16
just enjoying the outside.
17
things because too much heat makes me sweat, and
18
sweat flares my eczema.
I cannot do these
19
I have to stay inside all the time.
I have
20
always wanted to play baseball, but because it is a
21
summer sport, I cannot do it.
22
taking care of my skin.
It is a lot of work
And my parents have to
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163
1
help me a lot, taking bleach baths, applying
2
ointments and creams, and doing wet baths is really
3
hard.
4
One of my biggest fears is that I won't be
5
able to go away to college because I won't be able
6
to take care of my skin.
7
different dermatologists, and I've used over 18
8
steroid ointments, done light therapy and taken
9
oral medication, and nothing has worked.
I have been to six
That is why it is important that you allow
10 11
testing of new drugs for children.
12
suffering every day, and we are counting on you to
13
help us get some relief. DR. DRAKE:
14
Wow.
We are
Gracie and Isaiah, can I
15
tell you how proud I am of you for coming?
16
Eloquent, both of you.
17
persuasively that I don't think anybody on this
18
panel could vote against either one of you.
You presented your cases so
19
(Laughter.)
20
You're amazing, both of you, and thank you
21
for coming, and thanks for sharing your story with
22
us.
We really appreciate it.
A Matter of Record (301) 890-4188
And now our job is
164
1
to see what we can do to help the two of you, as
2
well as everybody else who suffers from this
3
disease.
4
applause, and thank you so much.
5
brave of you to come.
Dr. Eichenfield.
Next?
You got trouble.
DR. EICHENFIELD:
8 9
It was really
You're going to have a hard act to follow
6 7
So I'd like to give you a round of
them.
Really hard to follow
So I'm Larry Eichenfield, a pediatric
10
dermatologist.
11
discuss the timing of initiation of pediatric
12
studies in atopic dermatitis patients today on
13
behalf of Regeneron/Sanofi, as well as myself.
14
I appreciate the opportunity to
So I serve as a pediatric dermatologist at
15
University of California, San Diego.
16
was sponsored with Regeneron with reimbursement for
17
time and travel cost.
18
Pediatric Dermatology Research Alliance, which did
19
submit a position document to DODAC for
20
consideration.
21 22
Today my talk
I also am co-chair of the
I'm co-chair of the Eczema Center at Radiology Children's Hospital in UCSD and I'm a
A Matter of Record (301) 890-4188
165
1
member of several organizations and advisory
2
committees, which really reflects my longstanding
3
interest in atopic dermatitis.
4
I'm going to discuss briefly the high, unmet
5
medical need, which has been discussed so well by
6
Dr. Lindstrom and others this afternoon; the
7
perspective on timing of initiation of clinical
8
trials with systemic agents for children and
9
adolescents, and a little bit just to remind us
10
that atopic dermatitis, while similar to adults in
11
many ways, is also dissimilar, especially in our
12
access to medication, systemic medications, that
13
are approved for use of which they're quite
14
limited.
15
So we discussed the prevalence of atopic
16
dermatitis.
17
studies, looking at United States' populations;
18
similar to that in other industrialized countries
19
around the world.
20
We know it's 15 to 20 percent in most
We've heard about the significant proportion
21
of children who have severe disease with ranges
22
from 7 percent in Jonathan Silverberg's studies to
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166
1
18 percent in the Hanifin Study.
2
practice, probably 10 percent of my patients have
3
very severe atopic dermatitis.
4
patient who have moderate, severe, persistent
5
dermatitis requiring essentially constant
6
medication for control of the disease.
7
In my own
Another 15 to 20
We know about the impact; we've seen some of
8
the data today on the quality of life impact of
9
atopic dermatitis.
We've heard about it in our
10
patients.
We see this all the time in our clinical
11
practice.
We see children whose sleep is
12
tremendously disturbed.
13
We see impact on their school performance.
14
Impact on their social interactions, the
15
psychological and social development.
16
just the child, it's the parents and the family as
17
well who have to adapt to atopic dermatitis in the
18
household.
19
And it's not
We've heard about the comorbidities and
20
complications of the disease.
21
significant, both the traditional atopic
22
comorbidities, asthma or allergy, and increased
A Matter of Record (301) 890-4188
These are
167
1
risk for development of food allergy.
2
a complicating factor and exacerbates the disease,
3
as well as the potential psychological effects and
4
neurologic effects that have been associated and
5
the economic effects that have been estimated at
6
half a million to $3.8 billion a year on the U.S.
7
economy.
8 9
Infection is
We know that we've discussed this afternoon the limited armamentarium that we have;
10
predominantly a topical armamentarium and to date
11
with the only systemic treatment being topical
12
corticosteroids.
13
defaults that we use for systemic therapy having
14
significant known side effects and toxicities.
15
The products that we use, the
I'm happy to say that it seems that the
16
medical community that knows eczema best are pretty
17
aligned in their perspective, so when the Pediatric
18
Research Derm Alliance put together a position
19
paper, a lot of people fell behind it.
20
statement in the paper states that given the high
21
unmet need for effective and safe therapies in
22
atopic dermatitis in children, that pediatric
A Matter of Record (301) 890-4188
So the
168
1
studies with systematic therapy should be initiated
2
early in the drug development process, as long as
3
there are no safety signals that would raise
4
particular concern in pediatric-aged patients.
5
This was signed not just by the Pediatric
6
Derm Research Alliance, but by the American Academy
7
of Dermatology, the Society for Investigative
8
Dermatology, the AAD's Atopic Derm Expert Resource
9
Group, the National Eczema Association Scientific
10
Committee, the American Contact Dermatitis Society,
11
and the International Eczema Council.
12
A proposed criteria for initiation of
13
pediatric development of systemic agents in atopic
14
dermatitis is proposed.
15
safety profile in phase 1 and 2 studies of adult
16
patients in atopic derm, there's demonstration of
17
efficacy across the completed clinical trials in
18
adults using validated outcome measures, and no
19
anticipated significant pediatric specific concerns
20
based upon the drugs mechanism of action and
21
preclinical data, it seems appropriate to go ahead
22
and study this in children.
So if there's favorable
A Matter of Record (301) 890-4188
169
1
So on behalf of Regeneron, Sanofi, myself,
2
the tens of thousands of dermatologists and
3
pediatric dermatologists who signed on to the
4
statement, and more importantly, the tens of
5
thousands of patients who we care for, I hope the
6
committee understands the desire to include
7
children and teenagers with atopic dermatitis in
8
studies of systemic therapy as soon as reasonably
9
possible.
10
Thank you.
DR. DRAKE:
Thank you very much.
11
speaker number 5 come forward?
12
DR. TOLLEFSON:
Good afternoon.
Would
I'm
13
Dr. Megha Tollefson.
I'm a practicing pediatric
14
dermatologist at the Mayo Clinic in Rochester,
15
Minnesota.
16
the American Academy of Pediatrics, which is a
17
non-profit professional organization of 62,000
18
primary care pediatricians, pediatric medical
19
subspecialists, and pediatric surgical
20
subspecialists dedicated to the health, safety, and
21
well-being of infants, children, adolescents, and
22
young adults.
I'm here today speaking on behalf of
A Matter of Record (301) 890-4188
170
I was also a lead author on the recent
1 2
American Academy of Pediatrics clinical report on
3
atopic dermatitis.
4
already heard today, but I appreciate the
5
opportunity to provide comments on behalf of the
6
AAP.
7
A lot of what I will say, we've
We've heard that atopic dermatitis carries a
8
significant burden, both medically and
9
psychosocially.
Its prevalence is increasing in
10
the United States.
11
suffer immensely, as we’ve heard from two patients
12
right here.
13
have disease that can be controlled with our
14
standard topical treatments, but up to 25 percent
15
have severe disease that's difficult to control
16
with topical treatments.
17
Children with atopic dermatitis
Many children with atopic dermatitis
Despite this, there are no systemic
18
medications that are currently approved for the
19
treatment of children with atopic dermatitis in the
20
United States.
21
development of systemic medications to treat atopic
22
dermatitis in children with inadequate response to
As this committee considers the
A Matter of Record (301) 890-4188
171
1
topical prescription therapy, the AAP provides the
2
following comments.
3
First, the FDA should encourage the study of
4
the efficacy of systemic medications in the
5
treatment of pediatric atopic dermatitis.
6
treatments are largely limited to topical
7
treatments such as moisturizer, topical steroids,
8
and topical calcineurin inhibitors.
9
Approved
However, a recent survey indicated that the
10
majority of pediatric dermatologists use systemic
11
medications to treat severe atopic dermatitis
12
that's not controlled with skin directed therapies.
13
The systemic medications that are most commonly
14
used, we've already heard about today, specifically
15
cyclosporine, methotrexate, mycophenolate mofetil,
16
azathioprine, and prednisone.
17
These have not been studied in systematic
18
fashion regarding their efficacy in pediatric
19
atopic dermatitis.
20
studies exist even in the adult literature
21
regarding the use of these medications in atopic
22
dermatitis.
Very few randomized control
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1
There are no high quality, controlled trials
2
in pediatric literature, and adult experience is
3
often extrapolated to use in children.
4
there's a high rate of relapse of the skin disease
5
when patients, including children, are taken off of
6
these commonly used systemic medications.
7
Further,
Second, the FDA should encourage the study
8
of the safety of systemic medications in the
9
treatment of pediatric atopic dermatitis.
The
10
systemic medications that we've heard about today
11
have potentially serious and potentially
12
irreversible side effects in children.
13
about some of these side effects already, including
14
hypertension and kidney toxicity with cyclosporine,
15
bone marrow suppression, and liver toxicity with
16
methotrexate and azathioprine, hypertension with
17
mycophenolate mofetil, and diabetes, hypertension,
18
osteoporosis, and stunting of growth with
19
prednisone.
20
We’ve heard
Because of these potential side effects and
21
the questionable long-term safety and efficacy of
22
these medications, it is increasingly important to
A Matter of Record (301) 890-4188
173
1
develop newer safe and effective systemic
2
medications for children with severe atopic
3
dermatitis. Third, the FDA should consider early
4 5
inclusion of children in clinical trials where
6
systemic medications for the treatment of atopic
7
dermatitis are being studied.
8
urgent need for new therapies for children with
9
atopic dermatitis, we urge the FDA to work toward
Because of the
10
labeled pediatric indications for system therapies
11
for atopic dermatitis by encouraging the earliest
12
possible safe inclusion of children in relevant
13
trials.
14
Last, the FDA should consider the potential
15
impact on quality of life in children and families
16
when studying medications for systemic treatment of
17
pediatric atopic dermatitis.
18
it has a profound effect on the quality of life of
19
affected children and their families.
20
As we've heard today,
Nearly half of children who have atopic
21
dermatitis report a severely negative effect of the
22
disease on their quality of life.
A Matter of Record (301) 890-4188
The factors that
174
1
contribute to this severely negative impact are
2
fatigue and sleep deprivation, which are in direct
3
correlation with itching and severity of the
4
disease, activity restriction, and depression.
5
Children with atopic dermatitis tend to have
6
fewer friends and participate in fewer group
7
activities, which may put them at higher risk for
8
mental health disorders such as depression and
9
anxiety.
These findings illustrate the need for
10
urgent development of safe and effective systemic
11
medications to treat pediatric atopic dermatitis.
12
Thank you for this opportunity to provide
13
comments.
14
with the FDA to improve atopic dermatitis therapies
15
for children.
16 17
We look forward to continuing to work
Questions to the Committee and Discussion DR. DRAKE:
Thank you very much.
This
18
concludes the open public hearing portion of the
19
meeting.
20
let's talk about exactly what we want to do now.
21
We have about an hour left before people
22
And so the committee -- first of all,
start pulling out their chairs and running for
A Matter of Record (301) 890-4188
175
1
airplanes.
2
that's what's going to happen.
3
capture the most information I can within the next
4
hour.
5
Having been here many times, I know So I want to
We have six questions to address.
They're
6
not votes, but they're questions.
And so in
7
consultation with the FDA -- with my Lieutenant
8
Commander next door and others, in
9
consultation -- it seems to me probably the best
10
way to do it is to put each question up.
11
going to allow 10 minutes per question, which will
12
take us through the hour.
13
And I'm
If you have a pertinent comment, criticism,
14
suggestion, please get directly to the question.
15
Let's not cross-dialogue.
16
cross-dialogue, it would be really more fun if we
17
could do it, but we just don't have time.
18
In other words, the
So what the FDA wants to capture from
19
us -- and you guys correct me if I'm wrong.
20
what you want is information from us about some
21
possible answers and guidance and direction from
22
our opinions on your six questions.
A Matter of Record (301) 890-4188
But
176
1
Is that correct?
2
DR. MARCUS:
3
make one proposal.
4
DR. DRAKE:
5
DR. MARCUS:
Yes, although I would like to
Sure. In light of the eloquent
6
presentations during the open public speaker
7
session from Gracie and Isaiah, that we acknowledge
8
that there is an unmet medical need, and move right
9
on to question 2. DR. DRAKE:
10
I couldn't agree with you more.
11
I think those first -- a matter of fact, I think
12
question -- do I hear any opposition from the
13
committee that there's an unmet medical need?
14
(No response.)
15
DR. DRAKE:
16
DR. GASPARI:
Boom, that's done. Just one, sorry.
So now we -Related to
17
the unmet medical need, I wouldn't limit it to
18
drugs and biologics.
19
alternative therapies like probiotics, along those
20
lines.
21 22
DR. DRAKE: consideration.
Things like consider
Okay.
You'll take that into
Now before we start, I just wanted
A Matter of Record (301) 890-4188
177
1
to get the process underway.
2
the one person we haven't heard from -- and
3
remember I told you at the beginning, nobody gets
4
away from the table without commenting.
5
is really important that we have the patient
6
representative, Danielle Boyce.
7
But before I do that,
And this
So I'm going to ask Danielle Boyce to give
8
us an opinion, because she's been very quiet this
9
afternoon, and I think we have to hear from the
10 11
patient representative. MS. BOYCE:
We've heard from patients very
12
eloquently.
13
I had the disfiguring form of atopic dermatitis as
14
a child, and in the 70s, and what the options were
15
back then.
16
for baby pictures, so I don't have any, because my
17
mother was so disturbed by how I looked.
18
I don't know if I can follow them, but
And there also wasn’t any airbrushing
I've mostly outgrown it, but my daughter has
19
a mild form.
And one of the things that I think
20
that I would also consider bringing my child, my
21
young child in, given the fact that this does start
22
off in very young, and it's a terrible course up to
A Matter of Record (301) 890-4188
178
1
age 12 when we're talking about bringing these
2
children in.
3
and as a patient, to wait to start studying or to
4
start enrolling.
That's a long time to me as a mother,
One of the considerations is the
5 6
institutional review board.
You know if I'm
7
bringing my child into my hospital, to Children's
8
Hospital Philadelphia, I have faith and trust in
9
the institutional review board and in my clinician.
10
So if this decision has been made in
11
conjunction with my clinician with the approval of
12
the institutional review board, younger for me is
13
better.
14
DR. DRAKE:
Babies?
Infants?
15
MS. BOYCE:
If the safety and efficacy data
16
is there, and our physician and institutional
17
review board are comfortable with it, yes.
18
DR. DRAKE:
Okay.
Thank you.
19
MS. BOYCE:
That's a big if.
20
DR. DRAKE:
No, but I mean it's important.
21
MS. BOYCE:
Yes.
22
DR. DRAKE:
Thank you very much, Danielle.
A Matter of Record (301) 890-4188
179
1
I appreciate -- by the way, thanks for being here
2
today.
3 4 5
MS. BOYCE:
Thank you for having me [off
DR. DRAKE:
Now before we start down this
mic].
6
path of -- I'm still going to try to allow 10
7
minutes per question, because then, I've just
8
remembered I have to do a summation.
9
Dr. Marcus, you wanted to do a charge to a
But I think,
10
committee.
11
given -- skip question 1.
12
want me to do for sure, the committee as a whole,
13
what you want us to do with the rest of them,
14
questions 2 to 6 please.
15
I mean part of it's already been
DR. MARCUS:
But tell me what you
I'm just looking forward to an
16
interesting discussion and feedback on everything,
17
all of the aspects of pediatric drug development
18
for this indication, based on the presentations and
19
discussion people have already heard.
20
So with that, and the limited time we have,
21
I would say to continue with the questions and move
22
on to the questions.
A Matter of Record (301) 890-4188
180
1
DR. DRAKE:
Okay.
2
DR. BERGFELD:
Thank you.
Yes, Wilma?
I would like to suggest on
3
question 2 that the committee vote.
4
three options that are given, and then discuss once
5
we see how that comes out.
6
DR. DRAKE:
7
really want a discussion.
I cannot ask for a vote.
8
DR. BERGFELD:
9
discussion if there's a vote.
10
DR. DRAKE:
There are
They
I know, but we can focus our
Well, let me just ask for
11
consensus.
Would that be satisfactory if I use
12
consensus instead of vote, because I don't think we
13
want votes.
14
LCDR SHEPHERD:
15
DR. DRAKE:
We can't switch it to --
No, I said we can't.
Okay, and
16
besides I can't.
17
it, but number two I can't, so that solves that.
18
You see, she's a lieutenant commander for a reason.
19
Number one, I don't want to do
So here's the deal.
If you don't know, if
20
you haven't seen all the questions, look in your
21
book on page 36, 37, and 38 are all -- the
22
questions are all there -- so that you can think
A Matter of Record (301) 890-4188
181
1
about which ones you want to speak up on, because
2
not everybody can obviously speak on every
3
question, and not everybody can say everything
4
that's on their mind, so be selective.
5
Now that everybody's spoken, I'm not going
6
to force you to speak if you don't want to.
7
going to, but I was also told I probably shouldn't
8
do that.
9
don't want to put anybody on the spot.
10
I was
So what I'm going to -- that's because we
If you don't have anything you don't want to
11
say, we don't want to force you to say something
12
when it comes to decision-making.
13
discussion on question number 2, please.
14
Dr. Bergfeld?
15
DR. BERGFELD:
So I'm open for
Well since I was denied my
16
first recommendation, I would like to say that I
17
feel that the situation on atopic dermatitis and
18
the treatment of young children has been
19
established.
20
the unmet need, the need to treat earlier and to
21
use safe, as safe as we can, products.
22
I think that we clearly established
So I would like to support the preliminary
A Matter of Record (301) 890-4188
182
1
efficacy and safety data early phase trials in
2
children.
3
DR. DRAKE:
Is there anybody who would speak
4
against support?
5
summarize some of this, and if I'm wrong you can
6
correct me.
7
out loud, so let's just do that.
8
Thank you very much, because I should have thought
9
of that.
10
I get a sense -- I'm going to
I'm told we need to read the question No, that's fine.
So I'm going to read the question out loud
11
for the record.
12
evidence of treatment effect and safety should be
13
obtained in adults prior to studying the use of a
14
novel agent in the treatment of children with
15
atopic dermatitis that is inadequately responsive
16
to topical therapy with respect to primary [sic]
17
efficacy and safety data, early phase trials?
18
Please forgive me.
Determinative efficacy and safety data,
19
phase 3 trials?
20
So that's question 1.
21
what I heard from the committee.
22
How much
Post-marketing adverse event data? Now I'm going to summarize
What I've heard from the committee sort of
A Matter of Record (301) 890-4188
183
1
is that everybody's very much in favor of clinical
2
trials in early phase patients.
3
first part of that is yes.
Agree?
So the
The second thing, do you want to wait until
4 5
phase 3 or post-marketing adverse event data?
6
mean I think I'm hearing that -- I'm hearing heads
7
shake.
I'm hearing no.
8
DR. TOWBIN:
9
DR. DRAKE:
Yes, sir?
May I make a comment? Please.
10
DR. TOWBIN:
11
questions across the board.
12
be a little different than what --
13
DR. DRAKE:
14
DR. TOWBIN:
15
I
I have trouble answering these And what I heard may
Well, please, yes, please. What I heard may be a little
different than what you heard.
16
DR. DRAKE:
Okay.
17
DR. TOWBIN:
But what I heard was that this
18
was a drug-by-drug consideration, as opposed to all
19
comers, and that the considerations that we're
20
raising here in these three bullet points, really
21
would be specific to each agent.
22
DR. DRAKE:
Okay.
Yes, and I don't think
A Matter of Record (301) 890-4188
184
1
you're incorrect in that.
I think it goes -- I
2
heard two additional things.
3
drug, but the disease, and that, in other words,
4
we're looking at how serious the disease is and how
5
much difficulty the patient's in.
6
you're right.
7
board.
8
that we're taking into consideration the disease
9
state, the severity of the disease, when you take
I heard not only the
So I think
I didn't mean to say it's across the
I'm just trying to say that with the caveat
10
that into consideration that the notion would be
11
that early stage studies would be appropriate? DR. TOWBIN:
12
Well, I think for me what I
13
would want to be thinking about is this evidence of
14
efficacy and safety would have to be a factor
15
there.
16
see more data before you move to study them in
17
children.
18
from what you learned in phase 2.
19
couldn't really say across the board.
For some drugs, you actually might want to
For others, there might be reassurance
20
DR. DRAKE:
21
DR. TOWBIN:
22
And so I
Okay. I think in terms of severity, I
think that the structure of the study will require
A Matter of Record (301) 890-4188
185
1
benchmarks with good -- and a rate of reliability
2
and appropriate measures so can you can actually
3
make comparisons across studies and populations.
4
DR. DRAKE:
Okay.
What I'm going to
5
do -- because we're going to dive right out of
6
discussion on this.
7
being a ringleader on that, and I'm going to quit
8
it because I think -- I really wanted -- I'm going
9
to go back to my original plan, and that's have
And I've already started to
10
each of you offer comment.
11
listen carefully.
12
And then I'm going to
At the end of the listening period, I'll try
13
to summarize the comments instead of commenting on
14
each one.
15
through comments, and then I'll try to summarize at
16
the end.
17
Dr. Brittain?
18
So let's just raise your hand, we'll go
And so I've got the list here.
DR. BRITTAIN:
Well, echoing the seeming
19
consensus that I agree that trials should be done
20
as early as possible, because it's important that
21
we capture that window of opportunity when you
22
could still do randomized trials before off-label
A Matter of Record (301) 890-4188
186
1 2
use is done. I guess the one thing that I haven't really
3
heard that might be helpful is that within a trial
4
there could be an interim analysis done that would
5
allow reducing the age range in the trial.
6
doesn't have to be one trial, a trial in adults,
7
and then a trial that goes down to 12, and then a
8
trial in children, I mean younger children.
9
So it
You could start with adults, and within the
10
same trial if things look safe, then open it up to
11
a younger age group.
12
sort of doing it in a staggered fashion but not
13
necessarily waiting for phase 3.
14
DR. DRAKE:
So it's just a strategy for
Okay.
And Commander, would you
15
please remind me when the 10 minutes are up?
16
Dr. DiGiovanna?
17
DR. DiGIOVANNA:
Yes, John DiGiovanna.
Okay.
I
18
think I wanted also to reiterate what
19
Dr. Roth-Cline had said, and that's that there's a
20
window of opportunity.
21
my other part of that comment in that I think all
22
of these things apply.
Dr. Towbin I think caught
I think one would want to
A Matter of Record (301) 890-4188
187
1 2
start as early as possible when it's feasible. Then if there are novel trial designs that
3
allow interim analysis and starting early, then one
4
might expect before the end of trial that should be
5
incorporated.
6
are not identical to adults.
7
of post-marketing data or phase 4 data is more
8
important in this population.
9
these studies should have incorporated into them,
But the other thing is that children And I think the issue
And I think many of
10
depending upon the age of when the enrollees are
11
brought into the study, a period of looking for
12
post-marketing surveillance to look for
13
unanticipated side effects in the pediatric
14
population that might not be observed in the adult
15
population.
16
DR. DRAKE:
Dr. Maloney?
17
DR. MALONEY:
I, in listening to all of
18
this, I think it's very clear that everyone agrees
19
that one looks at the initial safety data from the
20
very early clinical trials and then move into the
21
pediatrics as soon as is practicable, and following
22
very closely.
A Matter of Record (301) 890-4188
188
I think that one of the things that we can't
1 2
allow to happen any longer is the endless waivers
3
and the deferrals that have gone on, because it is
4
difficult or a little harder; and that we need to
5
be very proactive in pushing so that there aren't
6
deferrals and waivers, and that we actually start
7
collecting data and doing the studies so that kids
8
get a break. DR. DRAKE:
9
Dr. Kopelman?
DR. KOPELMAN:
10
Right, sorry.
My thoughts were very much
11
along of Dr. Towbin's.
I would be much more
12
comfortable if I was looking at a particular study
13
rather than speaking in such general terms.
14
have a group that does not respond well.
15
have a study in front of us.
16
risks, and we speculate that there will be a
17
benefit, and it's just a little too vague for me.
We
We don't
We don't know the
I can certainly agree with the concept, as
18 19
early as is safe, but I don't know how to translate
20
that into voting without looking at a particular
21
study.
22
DR. DRAKE:
Dr. Cohen?
A Matter of Record (301) 890-4188
189
DR. COHEN:
1
Just to ask if there's quite a
2
bit of data out there already when it's used on
3
many of these drugs in other pediatric settings.
4
And so, I would ask that something that could be
5
done hopefully relatively quickly that would make
6
you feel better. Then as said, if we had at least some safety
7 8
data in other disorders where these drugs are used
9
on a regular basis, that would be helpful.
And
10
then at least if we could try to request that those
11
folks who are using these drugs already in this
12
setting could provide us a little bit of data on
13
say efficacy in children.
14
in adults -- I don't read the adult literature
15
much, but if there's much in adults out there
16
already, we could certainly look at that.
And if there is anything
But again, I'm more concerned about adverse
17 18
events.
19
there that we could glean from our colleagues from
20
other pediatric subspecialties, today, now.
21 22
And I think there's a lot of data out
DR. ROTH-CLINE: Roth-Cline.
This is Michelle
I'm going to interject here and just
A Matter of Record (301) 890-4188
190
1
make one clarification to address some comments by
2
Dr. Towbin and Dr. Kopelman.
3
absolutely this would be a product-by-product
4
discussion certainly.
And that is,
5
But I think part of the question here is
6
really what the default position ought to be for
7
these products.
8
warranted, based on whatever the safety and
9
efficacy data are.
And deviations from that can be
But I think what we're really
10
trying to ask is the default position that studies
11
in children should be deferred until after there's
12
adult post-marketing safety data, or is the
13
default, should the default position be that we
14
should start pediatric studies let's say at the end
15
of phase 2 in adults.
16
DR. DRAKE:
I mean I'm making stuff up.
No, but I actually know what
17
information you're trying to gather.
18
I'll try to capture that in the summary.
19
you for interjecting because that was important,
20
and I will try to capture that in the summary,
21
because I think I know -- you guys are looking for
22
a global approach that doesn't denigrate looking at
A Matter of Record (301) 890-4188
I get it.
So
But thank
191
1
an individual drug and the specifics of that
2
individual drug or indication.
3
DR. MARCUS:
4
DR. DRAKE:
5
DR. MARCUS:
Yes, I got it.
May I just add briefly to that? Sure. And I want to again refer to
6
one of the open public speakers.
7
some very pointed and relevant comments.
8
first public speaker, I've forgotten her name -DR. DRAKE:
9
I think I heard And our
Gracie.
10
DR. MARCUS:
I'm sorry?
11
DR. DRAKE:
12
DR. MARCUS:
13
speaker -- yes, I'm sorry.
14
DR. DRAKE:
Gracie. No, no.
Our very first Margaret.
Margaret, yes, I'm sorry.
You
15
can tell how much Gracie made an impression upon
16
me.
17
Go ahead. DR. MARCUS:
And I tried to quote you
18
directly, but you made a statement, and I'm
19
acknowledging you as both a parent of somebody of a
20
child with atopic dermatitis and as a researcher.
21
But you said that given the current products
22
available for -- children are better off in a
A Matter of Record (301) 890-4188
192
1 2
carefully monitored trial. I think that that probably represents in
3
this room someone who has carefully considered the
4
available products in an objective rational way
5
than anybody else.
6
safety -- and I shouldn't take away from all of the
7
other expertise in the room, but I think that
8
that's a bar that we can use.
9
who's emphasized we should be making a drug-by-drug
And so we have a lot of
And yes, I'm the one
10
consideration, but I think there's a bar for
11
comparison.
12
Dr. Cohen, I think you have stated we have a
13
lot of safety information available on the products
14
that are being used off-label, and that is
15
informative.
16
bar that we can be using in order to make an
17
assessment of what kind of risk might be tolerated
18
to enroll kids at what point in a development
19
program.
20
clarification or not.
And I think that's informative to a
And I don’t know if that's helpful
21
DR. DRAKE:
Okay.
22
comment is from Dr. Katz.
Thank you.
My last
My 10 minutes are up, so
A Matter of Record (301) 890-4188
193
1
Dr. Katz?
Last comment on the subject.
DR. KATZ:
2
Just I agree with
3
Dr. Roth-Cline's formulation, what the default is.
4
I think it should be the first one.
5
data suggest that there are safety problems,
6
particularly pediatric specific, then you go to the
7
next one, and then to the next one after that if
8
those problems persist.
9
should be the first. DR. DRAKE:
10
And if those
But otherwise, the default
Thank you.
Okay.
Question
11
number 3 we're going to.
12
much uncertainty about the -- can I have it up on
13
the screen?
14
please?
15
So the question is how
Is question number 3 up on the screen
How much uncertainty about the potential
16
risks and benefits of novel agents is tolerable
17
when initiating a pediatric trial, given the nature
18
of the disease, i.e., severity, comorbidities,
19
impact on quality of life, and the risk-benefit
20
calculus of available alternative treatments such
21
as the drugs that we've talked that have quite a
22
bit of toxicity, by the way, such as systemic
A Matter of Record (301) 890-4188
194
1
corticosteroids, cyclosporine, azathioprine,
2
methotrexate.
3
Anyway, address whether the enrollment of
4
pediatric subjects would be acceptable prior to the
5
resolution of questions regarding potential risk
6
for low frequency or long latency adverse events.
7
And by the way, that sort of focuses on your
8
question a minute ago, on the question 2.
9
really relating to that.
This is
So I assume you just want
10
us to kind of repeat your notion in the answer to
11
this question.
12
DR. TOWBIN:
13
DR. DRAKE:
14
DR. TOWBIN:
Yes, if you're talking to me. Yes, I am. This is Dr. Tobin.
I actually
15
think Dr. Marcus has given us a nice kind of way to
16
look at this first question, which is in comparison
17
to these other agents and what we know about their
18
safety profile, then as new agents come down the
19
pike, that would be the kind of measure, if you
20
will, the comparator, that we would want to be
21
thinking about.
22
To the degree that the safety profile looked
A Matter of Record (301) 890-4188
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1
similar or better than these current agents, then
2
one might be moved to look at something after
3
phase 2.
4
DR. DRAKE:
Thank you, Dr. Towbin.
5
comments on this question?
6
(No response.)
7
DR. DRAKE:
8
right.
9
questions then.
Whoa.
All
We just gained some time for other So let's increase the time to
10
12 minutes for the others.
11
committee?
12
Oh my goodness.
Other
DR. TOWBIN:
Questions for the
If I just could -- I'm sorry,
13
but I would like to make a comment about this
14
second question about whether enrollment of
15
pediatric subjects would be acceptable prior to
16
resolution of these other questions.
17
think that the design of the study will be critical
18
in the answer to that question.
19
Again, I
So what that means is how good the measures
20
are, how closely people are followed, what sort of
21
tail in the follow-up.
22
registries so that we can follow people quite a
Are we going to have
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1
distance out?
I believe all those things are going
2
to be important when we're talking about a
3
pediatric population.
4
DR. DRAKE:
5
DR. KATZ:
Thank you.
Dr. Katz?
I'd probably accept a fair amount
6
of uncertainty for a disease that has a lot of
7
morbidity.
8
before, the risk-benefit calculus of the available
9
alternative treatments is very difficult to figure
10
out right now because we don't know the dosing; we
11
don't know really the safety, and we don't know the
12
efficacy.
It's very prevalent.
And as we've said
13
So I think there's a fair amount of
14
uncertainty that should be tolerated, given what we
15
have in our armamentarium now.
16
For the second part of the question, I think
17
that it's hard to resolve those questions about the
18
potential risk for low frequency or long latency
19
adverse events without studying pediatric patients.
20
So I think it would be acceptable prior to
21
resolving those questions or else the advisory
22
committee in 20 years will be asking the same
A Matter of Record (301) 890-4188
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1
questions.
2
DR. DRAKE:
Same questions.
3
DR. GREEN:
I agree.
Yes, Dr. Green?
I think we all have
4
patients who -- some parents would accept certain
5
risks, and some parents wouldn't accept others.
6
all have people who don't even want to use topical
7
corticosteroids.
8
think if you were to ask a group of parents of kids
9
with bad atopic dermatitis, whether they're willing
We
So when it comes down to it, I
10
to accept -- I don't know, maybe their fingernails
11
might fall off or something like that, versus these
12
other side effects that come with cyclosporine.
13
Are you going to give them irreversible
14
kidney disease?
15
lines, you're really asking them.
16
sitting here, I have two kids, and one has very,
17
very mild eczema.
18
his behalf because his is very mild.
19 20
Are you going to -- along those And I think
I wouldn't accept much risk on
But as we've heard, I think if you ask -- I don't want to -- Isaiah, or I'm sorry, I forgot --
21
DR. DRAKE:
Gracie.
22
DR. GREEN:
-- I think if you asked them,
A Matter of Record (301) 890-4188
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1
they'd be willing to accept a lot more risk as may
2
their parents.
3
people to answer that question.
4
be part of the informed consent for them.
So I'm not sure we're the best
DR. DRAKE:
5
Yes, that's why we have informed
6
consent isn't it.
7
Dr. Corcoran?
8
was looking around.
Other questions?
Let's see.
Oh, down there at the end, sorry.
DR. CORCORAN:
9
I think it would
Gavin, of course. I think one other important
10
piece about this question is a couple of times the
11
point's been made today that children are not like
12
adults.
13
experience the disease differently.
14
I
They metabolize drugs differently.
They
I think if we're trying to sort out what the
15
benefit risk profile of the drug is, without
16
children being part of developing that benefit risk
17
profile, we'll end up with the wrong one.
18
especially the second part of that, you don't want
19
to wait until you resolve the issues in adults,
20
because in fact the benefit risk profile in
21
children may be completely different.
22
And so
So you may be developing a whole new benefit
A Matter of Record (301) 890-4188
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1
risk profile once you start to expose children to
2
the drug.
3
start to develop a well-rounded benefit risk
4
profile of the product, the better.
So I really do think that the sooner you
DR. DRAKE:
5
Okay.
All right.
6
is on my list.
7
appropriate pediatric population in whom to study
8
systemic treatments such that the risks and
9
potential benefits of the investigational agent
10
could be compared to the population who receive
11
alternative treatments.
12
prior treatment, age, and other relevant factors.
13
And I left out the alternative treatments, which
14
we've had listed many times.
15
systemic corticosteroids, cyclosporine,
16
azathioprine, methotrexate, and mycophenolate
17
mofetil, that's why I'm saying -- that's what I'm
18
trying to say.
19
Sorry, it's getting late.
20
Yes, Dr. Gaspari?
21
DR. GASPARI:
22
that.
Question 4.
Okay.
Nobody else
Describe the
Address disease severity,
For the record,
I just said it.
Good, thank you.
So I'd like to comment on
It is a basically moderate to severe
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1
disease, but the most important point I'd like to
2
make would be not necessarily just to limit it, say
3
if it's a novel biologic, not to limit it to
4
monotherapy. So the patient wouldn't be excluded say if
5 6
they're corticosteroid dependent.
7
basically combination therapy.
8
would be to consider that as an alternative to
9
broaden the scope of who would eligible for the
10 11
And then
So I would say that
study. Because I think it's too limiting just to
12
focus on monotherapy, and it's kind of a more of a
13
real world kind of approach that you have patients
14
that you're trying to transition therapies.
15
So I would take that into consideration in
16
terms of opening the realm of who would be eligible
17
or what you would be -- the kinds of questions you
18
would be studying.
19
DR. DRAKE:
So you're suggesting that if a
20
patient rolled in with topical steroid dependency,
21
but they weren't well-controlled, and then tried
22
some of these other things, you wouldn't stop
A Matter of Record (301) 890-4188
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1
everything at once.
2
DR. GASPARI:
3
DR. DRAKE:
Correct. In other words, a lot of
4
clinical studies, you have to stop everything two
5
weeks in advance --
6
DR. GASPARI:
7
DR. DRAKE:
8 9 10 11
Correct. -- and in this particular
population, that would be almost impossible. DR. GASPARI: DR. DRAKE:
Right. I mean just intolerable for the
patient so --
12
DR. GASPARI:
13
study arms to control or --
14
DR. DRAKE:
And there could be multiple
That's right.
You could do
15
multiple study arms to control, but we can't stop
16
the treatment on these kids.
17
DR. GASPARI:
Right.
But I would say open
18
the doors to more patients and have more arms in
19
the study to reflect the standards of practice, the
20
kind of patient that might move into such novel
21
therapy that might need it.
22
DR. DRAKE:
That's an important point,
A Matter of Record (301) 890-4188
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1
because most studies you have to stop all the
2
treatment and then start the drug, and it makes it
3
very tough, because especially on these kiddies
4
it's going to be almost impossible with this
5
disease.
Good point, Tony.
DR. BERGFELD:
6
Dr. Bergfeld?
I find this to be a very
7
complex question.
And I agree totally, it would be
8
moderate to severe atopic dermatitis of any age.
9
When you're comparing it to other drugs that you
10
have as example, we don't have really any studies
11
in those drugs, so that would have to be a whole
12
new arm on a study, and we'd be looking at two
13
drugs, efficacy and safety of two drugs at one
14
time.
15
DR. DRAKE:
Well, let me stand -- I don't
16
think Anthony was referring to these other drugs
17
that are not approved.
18
DR. BERGFELD:
I think he was talking -No, I understand what he was
19
talking -- this is the second question.
20
the same.
21 22
DR. GASPARI:
It's not
So along the lines of that
study -- so say a child is utilizing mid-potency
A Matter of Record (301) 890-4188
203
1
corticosteroids, so then they could be randomized
2
to a placebo or to the active agent and keep their
3
topical corticosteroid therapy.
4
it would add to the complexity and the layers of
5
the study.
6
facilitating, removing barriers for pediatric
7
patients to get enrolled in this study, that's what
8
I would promote, that approach.
9
And if necessary,
But again, I think in terms of
DR. BERGFELD:
I totally agree with you, but
10
I thought the study meant something new as compared
11
to something that's already being used, even though
12
it doesn't have good documentation in the
13
literature.
14
risks and the benefits of an investigational agent
15
could be compared to -- and then the comparison is
16
all the other drugs we've talked about today.
17
It says systemic treatment such as the
DR. GASPARI:
Right, but one of the
18
endpoints could be, so what is the value of the
19
novel biologic in lessening the dependence on
20
topical steroids, and being able to -- like grams
21
of corticosteroid used during the course of the
22
study in placebo versus active, along those lines,
A Matter of Record (301) 890-4188
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1
or whether systemic corticosteroids -- we do see
2
that in other clinical trials for diseases like
3
rheumatoid arthritis, and so there is precedent for
4
that approach, combination therapy. DR. DRAKE:
5
Okay, so Erica, I've got you
6
next, and then Kopelman, and then Green, and then
7
Cohen.
DR. BRITTAIN:
8 9
Dr. Brittain?
much to add.
Yes, I don't know that I have
It's just that if I understood
10
correctly you're basically talking about a study,
11
which someone who is on steroids would be eligible.
12
And it sounds like it's basically a stratification
13
factor, and that you would have placebo versus
14
drug, and some kids would be on steroids, and some
15
would not be, but it was just the stratification
16
factor.
17
patients jointly and separately.
18 19
And that allows you to study both types of
DR. GASPARI: to enrollment.
It's about removing barriers
I think that's the key.
20
DR. DRAKE:
21
DR. KOPELMAN:
22
Dr. Kopelman?
Dr. Gaspari's comment.
I just wanted to support Not only does it remove
A Matter of Record (301) 890-4188
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1
barriers, but I think it ensures that you'll get
2
compliance, because I can imagine a parent in the
3
trial maybe using the topicals anyway.
4
think that for compliance as well.
5
like to thank Michelle Roth-Cline for her comment
6
about the default position; that really clarified
7
it a lot for me.
8 9
DR. DRAKE:
So that I
And I'll also
Thank you. And Dr. Lindstrom, you have a
comment that addresses this?
10
DR. LINDSTROM:
11
DR. DRAKE:
12
DR. LINDSTROM:
A clarification actually.
Perfect, yes. Jill Lindstrom.
What we're
13
trying to ask with this question is describe the
14
population that you would consider for enrollment
15
in a trial of a systemic agent and looking at maybe
16
the obverse of the question is, describe the
17
population for whom you are using the alternative
18
systemic, available systemic therapies.
19
DR. DRAKE:
So Dr. Green, and then
20
Dr. Cohen.
21
you're going to say, plus that.
22
Maybe you can address those, whatever
DR. GREEN:
Sure, actually part of that,
A Matter of Record (301) 890-4188
206
1
then including people on topical corticosteroids,
2
if you notice all those charts that decreased
3
itching and decreased things, it didn't make it
4
zero; it just went down.
5
So it didn't make it go away completely.
So
6
I think continuing other therapies like that would
7
be important, because people going into it are
8
going to have to realize this is not a 100 percent
9
cure guarantee.
10 11
It's just going -- maybe it is,
but it's going to help make things better at least. Regarding the group that you wouldn't
12
include, I think people who are treatment naïve
13
might be -- like people who haven't used steroids
14
might be hard.
15
patients, too, who you've prescribed these things
16
that should have worked, and they didn't.
17
maybe one of those reasons is they didn't actually
18
use it, be it a corticosteroid, something along
19
those lines.
20
You know, I think we all have
And
I don't know how in the world you
21
would -- the studies have -- people have put
22
monitors on tops and things like that, to see if
A Matter of Record (301) 890-4188
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1
the tops have come off, and weighed tubes and
2
things like that.
3
address that going in, but I think someone who
4
hasn't been treated at all with anything that's
5
already -- you always want to maximize use of what
6
you have first, in addition to looking for new
7
things.
8 9
I don't know how you would
So I think not including people who haven't been treated with something before might be
10
important, kind of along the lines of what
11
Dr. Gaspari was suggesting.
12
DR. DRAKE:
Dr. Cohen?
13
DR. COHEN:
I was just going to say when I
14
consider a patient for a systemic agent, it's a
15
child who I know well.
16
consider on the first date.
17
children are on a complex regimen.
18
protective measures; we do allergen and irritant
19
avoidance.
20
It's not something I And most of these You know, we do
We're using topical corticosteroids.
We're
21
probably using topical calcineurin inhibitors.
22
We're using bleach baths.
We might be using
A Matter of Record (301) 890-4188
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1
intermittently topical antibiotics or oral
2
antibiotics.
3
So when we have a child who has been on that
4
regimen or this complex regimen for a period of
5
time that we think then warrants the consideration
6
of an oral agent, that's when a patient would
7
qualify, in our minds, for a study like this.
8
Most of these patients are going to be
9
severe disease, and occasionally moderate, but
10
usually severe disease.
11
generally speaking, these kids are over 2 years of
12
age, but there are some exceptions, because it
13
takes a little while to engage families with a
14
regimen like this.
15
I was going to say that
So again, if you see them at 5 or 6 months
16
of age, it may be 6 months or a year or 18 months
17
before you've exhausted all your aggressive, what I
18
would consider relatively conservative options,
19
before considering systemic agents.
20
Then all these other factors play in.
We've
21
done a couple of studies where we used the SCORAD
22
system and kind of like that, because it uses
A Matter of Record (301) 890-4188
209
1
clinical factors as well as family factors, sleep
2
factors, interference with the family dynamics and
3
the pediatric dynamics. But when you have a child who fails all
4 5
those things topically, then we would consider a
6
systemic agent.
7
pediatric dermatologists, but we do not use
8
systemic corticosteroids.
9
corticosteroids, and I think again, most pediatric
And I think I can speak for most
I never use systemic
10
dermatologists would not, unless there's a
11
life-threatening situation, which would be a very
12
different issue. So that would be the general criteria that I
13 14
would use to consider a patient for a systemic
15
agent.
16
to consider a pediatric patient for incorporation
17
into a study where I would look at a systemic
18
agent, either one of these older agents or a novel
19
agent.
That would be the same criteria I would use
20
DR. DRAKE:
21
DR. SIEGFRIED:
22
Dr. Siegfried? I don't think you have to
know a patient really well.
You know, that's
A Matter of Record (301) 890-4188
210
1
certainly the way we make that decision right now,
2
but I do think that we could come up with a set
3
criteria that are quantitative, even in the absence
4
of biomarkers, but there are certainly emerging
5
biomarkers that could be used in that regard.
6
So I think that there are so many details to
7
designing a good study.
And it took 15 years to
8
get good studies that were comparable for
9
psoriasis, and now we have them, but it took 15
10
years to get them.
11
enough the need for a guidance document.
12
And I again, can't emphasize
We could consider things like what is the
13
sleep deprivation that they're having, what are the
14
particular biomarkers that we could use.
15
of baseline evaluation would be required for their
16
immune system?
17
That's also very important in terms of the
18
phenotype.
19
What kind
What kind of history of infections?
What concomitant meds would be allowed or
20
not allowed in the study?
21
interim analysis?
22
important details.
What age stratification,
All these are important, really And I think with the right
A Matter of Record (301) 890-4188
211
1
group of people thinking it's not going be done
2
today. But to make a guidance document I think
3 4
would be an incredible incentive and useful kind of
5
a thing, and including comparator drugs as well.
6
Because even though we don't have data, we could
7
easily get it if we just had comparator arms. DR. DRAKE:
8 9
Dr. Towbin?
And then that's the
last one; we'll move to the next question. DR. TOWBIN:
10
Well, I just wanted to say all
11
of you seem to have a really good idea of what
12
you're talking about when you talk about moderate
13
to severe illness.
14
standardized measures that you could use across
15
trials that would work across age groups, because
16
if you're going to be doing this, you would want to
17
rely on those.
But I do hope that there are
For prior treatment, it's really clear to me
18 19
that everyone has a pretty good idea about what an
20
adequate dose for a sufficient duration of time
21
means.
22
spelled out.
And so I think those things could be I do have some concern about the
A Matter of Record (301) 890-4188
212
1 2
breadth of the age, from 2 to 12. I'm just not sure I feel quite right about 3
3
year olds and tweens being kind of all lumped
4
together as the same group.
5
imagine that you might want to think a little more
6
carefully about that.
7
DR. DRAKE:
Okay.
And so I just would
May I go to question
8
number 5, please?
Address the importance of having
9
sufficient data to label the product for use in
10
some or all pediatric sub-populations at the time
11
of an adult approval, in order to avoid the risks
12
of off-label use in children.
13
Dr. Siegfried?
14
DR. SIEGFRIED:
15
(Laughter.)
16
DR. DRAKE:
17 18
Any comments?
It's important.
Gotcha.
Yes, all right.
Dr. Bergfeld? DR. BERGFELD:
I believe also it's
19
important, but almost impossible because the
20
studies would have to be parallel studies.
21
there would have to be a release for the adult and
22
then an added label disclosure later probably, I
A Matter of Record (301) 890-4188
So
213
1
mean just by the timing of what you're going to be
2
doing.
3 4
DR. ROTH-CLINE:
So let me add one point of
clarification there.
5
DR. DRAKE:
Please.
6
DR. ROTH-CLINE:
And it really depends a lot
7
in certain cases.
8
necessarily need to get into today, but on whether
9
efficacy can be extrapolated.
10
And this isn't a discussion we
Because if you can extrapolate efficacy from
11
adults or at least partially extrapolate efficacy
12
from adults and abbreviate the efficacy studies in
13
children.
14
argument, at the end of phase 2 in the adult
15
development program, you can start earlier phase
16
pediatric studies, and then either at an interim
17
analysis in adult studies or concurrently with the
18
adult phase 3, you can do pediatric studies.
19
There have been in totally different
Then let's say, for the sake of
20
indications, precedents for that.
21
sort of a disease specific and product specific
22
kind of question.
A Matter of Record (301) 890-4188
But it really is
214
1
DR. DRAKE:
No other name?
2
(No response.)
3
DR. DRAKE:
All right.
We'll go to
4
question 6.
This one ought to be exciting.
5
Describe the age range that should be studied and
6
address whether older pediatric sub-populations
7
should be studied prior to or concurrently with
8
younger pediatric populations such as 12 to 17
9
years, or 6 to 12 years, or 2 less than 6 years, or
10
6 months less than 2 years.
11
on question 6?
12
Dr. Siegfried?
13
What is your opinion
Don't everybody speak at once.
DR. SIEGFRIED:
And again, I think we'd lose
14
an opportunity to recognize the efficacy of a drug
15
that could be way more efficacious in younger
16
children, if we deny that opportunity for something
17
that may not prove as effective in older people.
18
DR. DRAKE:
Yes, Dr. Cohen?
19
DR. COHEN:
Just some of the worst disease
20
we see are in those couple younger sub-populations.
21
So it would be crazy not to do that, because that
22
would be the population where our data would
A Matter of Record (301) 890-4188
215
1
probably be most useful. DR. DRAKE:
2
Pertinent to one of your
3
previous comments, potentially then some of the
4
adverse effects that go with the disease itself,
5
perhaps those could be headed off if you get to
6
patient early enough. DR. COHEN:
7
Absolutely.
I mean we would
8
definitely incorporate data looking at growth and
9
development.
You know, we could look at
10
percentiles for whatever parameters we would look
11
at.
12
DR. DRAKE:
Okay.
13
DR. COHEN:
It'd be easy.
14
DR. GASPARI:
So the great advantage to
15
including all the age groups, particularly the
16
younger age groups, is to address this overarching
17
question about altering the natural history of the
18
disease, the atopic march.
19
an opportunity if you don't include that sub-group
20
of patients.
21
what the risks and the benefits are across the
22
stratified age groups.
So you're really losing
So just stratify the age groups.
See
That would be my approach.
A Matter of Record (301) 890-4188
216
1
DR. DRAKE:
Yes.
Dr. Cohen?
2
DR. COHEN:
One other quick comment.
One of
3
the biggest mistakes that was made when the studies
4
were done with the topical calcineurin
5
inhibitors -- I know Dr. Eichenfield wrote a few
6
little -- it's interesting.
7
can find justification based upon studies in the
8
literature, well-done studies in the literature, I
9
can get a drug covered, even if it's off-label.
10
In our center, if I
So I have to fight all the time to get
11
topical calcineurin inhibitors for children under
12
the age of 3 or 2.
13
there that shows it's safe, but it would have been
14
a lot easier for us in terms of efficacy and in
15
terms of being able to provide something to these
16
special populations under the age of 2 where the
17
drug is not approved, where there certainly are
18
indications for use in sensitive areas.
And there is some data out
19
So I don’t want to see the same mistakes
20
made for systemic agents that were made with the
21
topical calcineurin inhibitors.
22
DR. DRAKE:
Okay.
I'm going to do something
A Matter of Record (301) 890-4188
217
1
a little off key here for a moment.
2
Dr. Eichenfield?
3
mic?
4
here and listened to all this, you really have a
5
ton of experience.
6
out of participating in the meeting because of your
7
many activities, but I think the committee would
8
benefit from hearing your opinion on some of these
9
fundamental questions.
10
Would you mind coming up to the
I want to pick your brain, because you've sat
And I know you were conflicted
DR. EICHENFIELD:
Would you mind opining? Well, thank you, and I
11
appreciate it.
I think the conversation today has
12
been tremendous.
13
FDA for such an approach, because it's totally
14
tremendous from a pediatric perspective to wrestle
15
with these issues in such a way.
And first of all, thanks to the
16
I do think that it's very nice to take an
17
approach that says, okay, let's figure out how we
18
can study these medicines early, and then you're
19
still going to be left on a drug-by-drug basis,
20
deciding at what point that you do that.
21
that's a very different approach than saying, Oh,
22
let's just take the conservative approach of
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218
1
waiting 10 years for safety data, and then we'll
2
look at it.
3
So I think that the medical need pushes for
4
us to get at that, and I still think there's always
5
going to be the hard wrestling done at the agency
6
to figure out what point with each drug do you drop
7
it down to a lower age.
8
start to get to younger ages, you're going to get a
9
little tougher in terms of your -- you should get
I do think that as you
10
tougher in terms of what you're calling severe
11
versus moderate to severe. I just think that's important, because it's
12 13
really that 8 percent that we want and not that
14
extra 20 to 30 percent, that high-body surface
15
area.
16
kids with high-body surface area in the younger age
17
groups, but we can maintain them with other
18
treatment regimens.
19
Most of our kids under 2, we've got a lot of
On the other hand, the question, the real
20
scientific question of are we going to have
21
tremendous disease modifying effect by treating
22
relatively younger kids with this disease and burn
A Matter of Record (301) 890-4188
219
1
out their disease earlier is something that's going
2
to take a lot of years to figure out, but I think
3
is really potentially something that we're going to
4
see in the next decade with these drugs.
5
So I thank the FDA again for the approach,
6
but I do think that the sort of where you're at
7
with the discussion with the committee right now,
8
is something that's highly, highly consistent with
9
where most of us who are living in the world of
10
pediatric atopic dermatitis day in and day out with
11
our families, would be very excited at the
12
conversation that happened today.
13
DR. MARCUS:
14
DR. DRAKE:
15
DR. MARCUS:
May I ask a question? Please. Just getting at the issue of
16
deciding who is appropriate to enroll in terms of
17
defining moderate to severe disease.
18
something I certainly would like to hear more
19
discussion about in terms of Dr. Cohen, as you
20
said, a patient you would consider enrolling in a
21
clinical trial is somebody that you know very well,
22
who has incorporated a complex regimen of treatment
A Matter of Record (301) 890-4188
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220
1
into their life. Yet, I get the sense -- and the part that I
2 3
haven't heard is there is still disease burden
4
that's significantly impacting the quality of life
5
of the patient and the family.
6
interested in hearing if you can better define who
7
those people are in terms of sleep disturbance,
8
quality of life, days of school missed.
And so I'm
9
Is there a population we can drill down on
10
that might better define who to enroll in clinical
11
trials?
12
DR. DRAKE:
Just a second.
13
DR. MARCUS:
14
DR. DRAKE:
Yes. I wanted to thank
15
Dr. Eichenfield for coming.
16
I'll take this back to the committee now.
17
you.
So thank
So now, I've got a list of Cohen, Cline,
18 19
Thank you so much, and
Hori, and Towbin. DR. COHEN:
20
Yes, so press on Dr. Cohen. I could answer you by saying I
21
know them when I see them, but that wouldn't be
22
fair.
We actually are lucky enough to have a
A Matter of Record (301) 890-4188
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1
pediatric psychologist to spend some time with us,
2
and she makes us do a SCORAD on every patient who
3
comes in, especially -- not on every patient, but
4
all the patients who are moderately or severely
5
affected.
6
So she has a pretty good sense -- we have a
7
pretty good sense of who they are, and it doesn't
8
take a long time.
9
them relatively frequently.
If they're severe, we're seeing And so I would think
10
in a period of a couple -- well, I shouldn't say,
11
but in a period of 3-6 months, we have a pretty
12
good sense of who those patients are.
13
In response to your query, it may be
14
reasonable to think about -- and I think this issue
15
was brought up earlier, to look at these scoring
16
systems.
17
I've used the SCORAD and the EASI score system.
18
Those have been most useful to us, and those both
19
incorporate clinical findings, and then the
20
psychosocial issues and the family issues.
21 22
Again, I've participated in studies where
We've only used those systems because our pediatric psychologist won't let us use anything
A Matter of Record (301) 890-4188
222
1
else.
But those systems allow us to come up with a
2
numerical number.
3
correlate with the kid who I know has bad disease.
And again, those usually
4
DR. DRAKE:
Doctor -- I'm sorry.
5
DR. ROTH-CLINE:
This is Michelle Roth-
6
Cline.
I want to pin you down on a couple of
7
points.
8
and try to design these studies, it really is
9
sitting down and getting into the nitty-gritty of
And one was when we at the agency sit down
10
who these kids are and who is appropriate to enroll
11
and who isn't.
12
So as specific as you're comfortable being
13
about what those children look like would be
14
enormously helpful to us.
15
The second thing is the question on number 6
16
was really not only should we enroll children,
17
let's say ages 2 to 6, but the real question is do
18
we have to study 12 to 17 year olds ahead of 2 to 6
19
year olds.
20
down the pediatric age range or not?
21
want the committee to be clear, please.
22
Do we need to do this sort of march
DR. DRAKE:
And I really Thank you.
I'm going to take the first stab
A Matter of Record (301) 890-4188
223
1
at it.
2
committee pretty uniformly say no, because each of
3
these age groups have different parameters.
4
somebody disagrees with that, speak now.
5
next.
6
I heard the committee say no.
I heard the
If
Okay,
Dr. Horii? DR. HORII:
You know in answer of your
7
question there, I think all the age groups should
8
be stratified.
9
things specifically, especially if you are going to
So you may be looking at different
10
be looking at the 6 months to 2 years.
11
new medication that hasn't been looked at in
12
children that young before -- I think doing PK
13
studies and pharmacodynamic studies and seeing how
14
the patients are going to be metabolized in this,
15
because dosing might be quite different for them at
16
that age.
17
And it's a
But then still looking at 2 to 6 year olds,
18
6 to 12 and 12 to 17, but do them all at once, but
19
maybe focusing a little bit more in certain age
20
groups on certain factors.
21
DR. DRAKE:
22
DR. TOWBIN:
Dr. Towbin? Yes, I just wanted to make a
A Matter of Record (301) 890-4188
224
1
plea that when you begin to do this kind of
2
stratification that you power the study
3
sufficiently so that you can really compare these.
4
It looks as if the criteria, actually the
5
eligibility criteria, might be different at
6
different ages, if I understood the comments
7
earlier.
8
So that's going to be important.
But what
9
often happens in pediatric studies, at least in
10
other specialties, is that you don't get good
11
representation across all of these different
12
strata.
13
way that you could actually make those comparisons
14
and see whether some of these hypotheses about the
15
march would be deferred, and so on.
And you would want to power this in such a
16
So the more that you lump them all together
17
2 to 17, the greater the risk that you're not going
18
to have that kind of power.
19 20 21 22
DR. DRAKE: the powering.
Yes, I think people get it about
I agree with you.
DR. KOPELMAN:
Dr. Kopelman?
Loretta Kopelman.
I think in
this case, because very young children are apt to
A Matter of Record (301) 890-4188
225
1
have the most severe forms, I'm very sympathetic
2
with that.
3
children before younger children.
4
sure I'm ready to give up that default after
5
discussing one disease.
But often the default position is older
6
DR. DRAKE:
7
DR. DiGIOVANNA:
8 9 10 11
Thank you.
I'm not quite
And Dr. DiGiovanna?
Perfect timing.
Dr. Kopelman, I'm going to try to help you do that. DR. DRAKE:
Wait, no, no -- yes.
want is not cross-discussion. DR. DiGIOVANNA:
Right.
What I
I want your opinion. So I wanted to just
12
reiterate a point that Dr. Eichenfield made.
13
talked a lot about the clinical disease.
14
haven't really talked about any mechanisms.
15
some of the collaborators of Dr. Drake at Harvard
16
have done a lot of work, Rachael Clark in
17
particular, about resident memory T-cells.
18
We
We And
These are T-cells that sit in the skin for a
19
very long period of time.
And if you can alter
20
that at an early stage of this disease, which may
21
not be possible in older children, you really have
22
a risk-benefit ratio that's very different, because
A Matter of Record (301) 890-4188
226
1
you may be able to arrest the disease, as Tony was
2
suggesting before, only in the younger children
3
that really may alter for a very long period of
4
time in the course of the disease. If you don't study those younger children,
5 6
you will not identify that.
7
you study the older children first, you will miss a
8
generation of potentially preventing the disease.
9
So I think you really do need to look at the
10
And if you wait until
risk-benefit ratio in each of these age groups. DR. DRAKE:
11
Boy, that was an important
12
point.
FDA, that should have really helped
13
clarify, because that really focuses the issue.
14
And you stated that very nicely.
15
DR. DiGIOVANNA:
16
(Laughter.)
17
DR. DRAKE:
18
(No response.)
19
DR. DRAKE:
Thank you.
Thank you.
Other comments?
All right.
Well, we're getting
20
very close to the end of the day.
21
supposed to summarize each question as we went, but
22
as you can see, that didn't work out very well.
A Matter of Record (301) 890-4188
So I was
I
227
1
tried that on the first question.
2
down.
3
overall summary, which I think will work better,
4
but specifically before we start down that path,
5
I'd like the FDA to have the opportunity to ask any
6
panel member any question or to the group as a
7
whole that would help you guys do your job better,
8
because that's been the purpose of this meeting is
9
to help you figure out how you want to proceed.
10
I got all bogged
So what I'm going to try to do is do an
Listen, while they're discussing that, I do
11
want to thank, first of all, the sponsors.
12
know, we haven't said much to you guys over there,
13
and we haven't called much on you this afternoon.
14
But I want to thank you personally and on behalf of
15
the committee and the FDA for bringing this issue
16
forward.
17
You
I know you expended time and considerable
18
resources and have put a lot of thought into this.
19
And so our goal here is to try to be helpful.
20
just because I didn't call on you every 5 minutes,
21
doesn't mean I wasn't very thoughtful about your
22
considerations and really wanting to help you move
A Matter of Record (301) 890-4188
And
228
1
forward, because I think you've brought really
2
important questions to this committee. It is time for kids to be considered.
3
You
4
know, we've done this before with women.
5
you've brought this issue and you forced the
6
committee to think about it.
7
thank you for doing it.
8
the sponsors, but I wanted to thank you for doing
9
this.
10
And now
And I just want to
So often we don't thank
I think it's an important opportunity, and
11
important question.
So thank you for your
12
diligence and your willingness to come forward with
13
these important issues.
14
everybody, thanks.
So just on behalf of
15
Now then, back to the FDA.
16
DR. LINDSTROM:
Yes.
Jill Lindstrom.
I'll
17
speak on behalf of my colleagues at the table.
18
while we don't have further questions to articulate
19
to the committee, I want to take the opportunity to
20
just express our sincere and profound thanks for
21
your participation today.
22
What you've said has been invaluable.
A Matter of Record (301) 890-4188
And
We
229
1
will receive a transcript.
2
back to it frequently to glean more nuggets than I
3
have written down and will retain in my memory.
4
But what I want to say is a deep and profound thank
5
you for your service and your input today.
6
DR. ROTH-CLINE:
I imagine I'll be going
And thank you as well to
7
all of the open public hearing speakers.
8
lot of advisory committee meetings, and this was a
9
really memorable open public hearing in a really
10
positive way.
11
spoke today.
12
I do a
So I want to thank all of you that
DR. DRAKE:
Okay.
Well I'm going to try to
13
do a wrap-up, and I want you all -- your work is
14
not done.
15
because if I miss something, we've got to add it.
16
All right?
17
agree with, we've got to correct it.
18
You have to listen to me carefully
Or if I say something that you don't
But I, too, want to thank -- first of all I
19
want to thank everybody who took your time out of
20
your day to come to the open public hearing and all
21
of the audience who's been here all afternoon.
22
really appreciate your participation and your
A Matter of Record (301) 890-4188
We
230
1
comments; extraordinarily helpful. FDA, thank you guys.
2
I mean, this whole day
3
has been exciting.
This afternoon was spectacular.
4
I mean it's just been a fabulous -- you've done
5
such a good job.
6
put together.
7
morning panel, but guess what?
8
it.
9
pulled some stuff out of the bushes here.
I mean, look at this panel you
I didn't think we could surpass the This one's equal to
It's just really, really good.
You really You
10
really beat the bushes and got the best people at
11
this table. It makes my job really easy as chair,
12 13
because I don't have to do much except just call on
14
names and try to keep people in proper order,
15
because you can see this group of professionals and
16
highly intelligent, committed, dedicated people
17
really put their effort into it, and so did you
18
all.
19
pleasant afternoon.
20
So thank you so much for making this such a
Having said that, I'm going to go through --
21
I'm not going to try to summarize question by
22
question.
That'll just take too much time.
A Matter of Record (301) 890-4188
But
231
1
with your permission, I’d like to just maybe
2
mention some high points just to reiterate some of
3
the high points, but this is where I need all of
4
the committee's help.
5
more notes here than I know what to do with; you
6
guys were so good.
All right?
Because I've got
So first of all, I think that there's
7 8
clearly an unmet need; that this absolutely has to
9
be done; that it's time to study children.
To
10
quote Mary Maloney, "It's time to give the kids a
11
break."
12
these children and what do they need, and how can
13
we help them.
14
And let's actually step down and look at
Our two kids from the open hearing group
15
were spectacular in bringing that to our attention.
16
It helped really focus us.
17
clinical trials on kids.
18
timing of the intervention, it came across clear to
19
me that timing is early, because you may -- not
20
early do you help the kids in that population.
21
kids are different in different populations, but
22
there is a potential that you can alter the course
So we do need to have And the whole question of
A Matter of Record (301) 890-4188
And
232
1
of the disease permanently, which would be huge if
2
that could be done. I don't think we'll know that, because we
3 4
have to have the data.
The second reason to do
5
clinical studies in children, is do we do as much
6
damage by not doing the studies, as we do by doing
7
them, and I would say the answer to that is
8
probably yes. Because ignoring them and not putting them
9 10
in well-controlled studies where they have good
11
monitoring and good data collection that we can use
12
for future reference, it's probably a mistake.
13
of course it has to be done with consideration,
14
according to the disease severity and what's gone
15
on.
16
But I think there's almost nothing to be
17
lost and everything to be gained if we do it
18
carefully and thoughtfully with the comments as
19
presented by the committee on how to do it
20
properly.
21 22
The other thing is what's happening now is -- another reason to do them is because right
A Matter of Record (301) 890-4188
And
233
1
now we're still treating them with toxic drugs, and
2
we're treating them with nasty things.
3
they're important drugs.
4
word.
5
I mean,
I shouldn't use that
We're treating with drugs that have some
6
toxicity.
7
They're being treated off-label.
8
gathering appropriate data to even identify what
9
those possibilities are.
10
We just don't know much about it. We're not
So by instituting formal trials to look at
11
some of these more serious questions, I think it
12
will not divert the populations to off-label use,
13
but rather put them into a pool where we can
14
collect data and gather information over time,
15
which will be very useful to everybody.
16
So I really think the time has come to look
17
at children.
I think it's a window of opportunity.
18
And what's happening is right now we're not -- I
19
did the original guidelines of care for the
20
American Academy of Dermatology, which was
21
terrible, because we had no evidence to base
22
anything upon.
It was all done by consensus.
A Matter of Record (301) 890-4188
It
234
1
was a bad time.
2
which is not ideal, because sometimes the consensus
3
isn't correct.
4
We had to just do it by consensus,
So what I see happening here in kids is
5
we're still doing a lot by consensus.
6
it's time to move more into evidence-based with the
7
kids, too.
8
extrapolation, I think that's been ruled out.
9
So that's important.
And I think
The
Now the other thing, let me move on to my
10
second page of notes here, is that the phase 4 I
11
think I heard somebody mention.
12
remention it because I think that's important.
13
phase 4 studies are going to be key in this area,
14
because each group is going to behave a little
15
differently.
16
I just want to The
It's going to be very important that the
17
stratification is there, that the power is there.
18
So when you actually stratify it, I think
19
everybody's in agreement studies should be
20
concurrent, because we don't want somebody to have
21
to wait eight years to have access to a really good
22
drug just because they're a kid.
A Matter of Record (301) 890-4188
They shouldn't be
235
1
penalized for being a kid. So we need to power them and do the studies
2 3
large enough to actually come up with things that
4
might help them.
5
said, maybe it was Mary again, we need to eliminate
6
waivers and deferrals, and I couldn't agree more.
7
Let's get this data collected.
8
pipeline so we can start making real decisions
9
based upon evidence.
I think the notion -- somebody
Let's put in the
Dr. Cohen, you repeated this more than
10 11
once -- thank you so much -- to look at other data
12
with these drugs in other diseases and in other
13
study populations, and even in adults.
14
don't really want to extrapolate, but we know a lot
15
about the toxicity from adults, plus you've pointed
16
out we know a lot about it with other diseases in
17
children.
I mean I
So we should look into those databases.
I loved Dr. Gaspari's point about removing
18 19
barriers to enrollment.
I think we're terrible at
20
that.
21
diseases because we need a purer system to evaluate
22
the new drug, but in fact, in this particular
We take people off drugs in all kinds of
A Matter of Record (301) 890-4188
236
1
population, we absolutely should not do that,
2
because these children are suffering, and we cannot
3
enhance their burden of suffering and preclude them
4
from participating in a trial.
5
clever ways to do it.
There's bound to be
In other words, if they're on a regimen
6 7
that's just not working and they're breaking
8
through, then keep them on the same regimen, but
9
add the new drug.
I mean I think there are ways to
10
design studies with thoughtful deliberation that
11
can address that without having to wash them out
12
for two weeks and make their life miserable, so
13
really to remove the barriers. I think the other thing is that, to me, the
14 15
most important thing that came out of this meeting
16
is that this stuff is on the table now.
17
actually seriously considering, and the FDA is
18
seriously considering, and the industry -- thank
19
you -- is seriously considering how can we do this
20
better.
21 22
We are
So that's kind of a high-level summary. What did I miss you guys think are really key
A Matter of Record (301) 890-4188
237
1
points that I might have left out? Whoa.
2 3
Strike 1 for Lynn.
I mean
that's -- oh, I knew it was too good to be true. DR. RAIMER:
4
No, it was mentioned before,
5
but just that the inclusion criteria may need to be
6
different for the different age groups in children.
7
Yes, so not just one set of criteria. DR. DRAKE:
8 9
very important.
Okay, yes.
Thank you.
We should stratify -- the
10
inclusion criteria should be different for
11
different age groups, absolutely.
12
Dr. Maloney's going to catch me, too. DR. MALONEY:
13
That's
And Go ahead.
No actually, I'm not.
I'm
14
going to thank you for doing such a good summary.
15
And in addition, to lending a sense of urgency,
16
which I think everyone at this table feels.
17
your summary gives us that sense of urgency, which
18
I think the FDA both shares and has heard from this
19
panel.
20 21 22
And
So thank you very much, Lynn. DR. DRAKE:
Well, thank you very much, Mary.
I appreciate it. Other comments?
A Matter of Record (301) 890-4188
238
1
(No response.)
2
DR. DRAKE:
Well, I tell you what.
3
have done a tremendous job.
4
everybody.
5
The meeting is adjourned.
6
You guys
Again, thanks to
Successful day and travel safe home.
Oh hold, I did it once before, and I almost
7
did it again.
My left-hand person, the Lieutenant
8
Commander here is amazing.
9
good job, and I just cannot tell you how important
She has done such a
10
it is for me at this table when I'm trying to track
11
everything, to have somebody who -- the old term is
12
you've got my back.
13
Well, she doesn't.
She has my left hand,
14
and she's making sure that everything runs
15
smoothly.
16
for a job well done.
17
So please give her a round of applause
(Applause.) Adjournment
18 19 20 21 22
DR. DRAKE:
Now the meeting is adjourned.
Thank you. (Whereupon, at 5:06 p.m., the afternoon session was adjourned.)
A Matter of Record (301) 890-4188
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