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PROPOSAL TO ADDRESS THE LACK OF PEDIATRIC LABELING FOR DRUGS
BACKGROUND
Children suffer from most of the same diseases as adults, and, by
necessity, are treated with most of the same drugs as adults.
The majority of new drugs and biological products, however, have
not been tested in pediatric populations. As a result, product
labeling frequently fails to provide directions for safe and
effective use in children, despite widespread use. An FDA survey
of drugs prescribed during 1994 identified the 10 drugs
prescribed most frequently to children without adequate labeling.
Together, these 10 drugs were prescribed more than 5,000,000
times. Because of differences in size and ability to metabolize
drugs, children require different doses than adults and may be
subject to different adverse reactions. The absence of pediatric
labeling information thus poses a serious risk of inappropriate
dosing and unexpected adverse effects in children. It may also
result in failure to provide children with optimal treatment in
cases where physicians are reluctant to prescribe potentially
toxic drugs to children before they have undergone pediatric
testing. For example, a survey by the Pediatric AIDS Foundation
found that fewer than 10% of children with AIDS were receiving
protease inhibitors, the newest and most promising AIDS drugs.
In recent years, FDA has undertaken several initiatives to
encourage the voluntary addition of pediatric use information to
drug labels. FDA has implemented a "Pediatric Plan" designed to
focus attention on and encourage voluntary development of
pediatric data during drug development. FDA has also identified
the top 10 drugs used in children without adequate labeling
instructions, and has written the manufacturers of these drugs
requesting that they submit supplemental applications to add
pediatric use information to their drug labels. In 1994, FDA
issued a new rule that allowed pediatric use information to
appear on label on the basis of substantially less data than
before, and that required manufacturers to survey existing data
to determine whether there was sufficient information to support
pediatric use information in the drug's label.
These voluntary efforts to increase the amount of pediatric use
information in labeling have not resulted in significant gains,
particularly with respect to new drugs entering the marketplace.
A comparison of drugs approved in 1991 and 1996 showed that
approximately 47% of the drugs approved in 1991 with potential
use in children had pediatric labeling, while 37% of those
approved in 1996 with potential use in children had pediatric
labeling.
total NMEs
potential
pediatric
post-
pediatric
Year
approved
use in
labeling
approval
labeling
children
at
study
later
approval
promised
submitted
1991
26
15
7
7
1
1996
53
40
15
17
?
PROPOSAL
FDA is considering proposing new regulations to address the lack
of pediatric use information by requiring, for the first time,
that applications for certain new drug and biological products
contain pediatric data. The purpose of the proposed rule would
be to ensure that important new drugs and biological products
carry adequate pediatric labeling at the time of, or soon after,
approval. The pediatric study requirement would be limited to a
small group of new drugs and biologics: new molecular entities
(the most innovative drugs) and biological products that (1)
would provide a significant therapeutic advantage to children
suffering from the disease or (2) would be expected to be used in
a substantial proportion of children. Pediatric studies could be
deferred until after approval if FDA found that it was
appropriate to delay pediatric studies until sufficient data were
collected in adults. The requirement could also be waived
altogether under certain circumstances.
The proposed rule might also codify FDA's authority to require in
compelling circumstances that manufacturers of already marketed
drugs and biological products conduct studies to support
pediatric use labeling. The circumstances in which FDA might
require pediatric studies of a marketed drug would be: (1) where
the drug is widely used in children and the lack of adequate
labeling poses significant risks to children, or (2) where the
drug offers a significant therapeutic advantage to children but
additional information is needed to permit safe and effective
use.
The absence of workable penalties has historically hampered FDA's
ability to require pediatric studies. It is inappropriate from a
public health standpoint to prevent the marketing of a drug that
offers a clinical benefit to adults simply because the
manufacturer has failed to study the drug in another subgroup of
the population. FDA is therefore considering a different type of
penalty for failure to conduct a pediatric study. FDA would take
the manufacturer to court and obtain an injunction requiring the
2
study to be completed. Violation of the injunction would be
punishable by contempt or fines.
3
Pediatric Drugs
3/20
meetin Zwks.
Weul induser Sproblen3
kasocbam lenos. of exclusivity for adults + kids
windfull in Some wres for both levis
to
patent St.ll up to company
gereris opposed it - -no floor or ante action
1994- FDA no drouble blind clinical tco ts for kids
just No 120,000
cost
peniatred page on applications
data no better than before
why not do it (firms) ? Don't know.
1. Culture - mind set
2. Formulation
3. Small markets + bei used already
F.rms Never mentor liability
1994 feg. sys we have the authority Is require it
PAF could 1 is a petron b/c believe we must do H
new Dr.gs:
FDA - hold in contempt of don't do study -woulday copal action to leg
olddrys competly WAL- servins discase, or welley prescribe
Actom: propose, public ats, final role
1/29
SOTO
Pedetric Drugs
/
Dake of Q.3 3
2.
9,000 indep. students we some of by
un republe
legner issue
FPA trut several Stabycs that did nt succeed:
epto 1: casier tr do a pedustre application -no roub test le I'd
1994: metor ange
-casier b 1. trials
fall
- 1.m.kel to most cosested into- - simple drug (cocl for
limited sceess
right lover 6. kins.
2. Pedetric page mapplication 3. Asled for ped.cato.
1996 - incentions -based i led exclusivity for those
who do there studies
geeric only concerns
we no not control
drawbucks to this approach wiffall
Spart: Mismatch befits rcost
want be ost.ch position
oblyahon k no infor kids ytubs w- w.h loit
£
WUH kg consider action
7
FDA reles on corpany to say purposes (who is berfuary:
1994 Act deciding Dec96 ?
1991
1996
26
53
New Molecular entities
15
40
potential ped. use
7
10
pediatric labeling
/ Prese IV studes
7
13
approved brequred. ped. data Babses
I
only ( followd through afred todo +
reg
pat-1994 date
- aprove w/ ry 7 lake lably
but wd have informant recours
- coube a presupts but new station
wd becare NDA
4>the 4>
put D-t for commet
Kissler words even code ase
where lisitle pediation plan
why not is
1.cost
2. no trush
3 liability
Sents HHS. +OMB
have UP mts 01 next 2mos
voluntry efforts
support reg.
Politics
- parents
- pherm - delay Most
but not hold
- Hill 2 don't know
Hustin
doing cost state
02-27-97 09:32AM
FROM FDA/OMO/IO
TO 92024562878
P003/005
CLOSE HOLD
HOT FORIBUT
DRAFT
IMPACT OF PEDIATRIC STUDY REQUIREMENT
FDA has made a very preliminary assessment of the impact of the
proposed pediatric study requirement. This assessment is based
on the assumption that the requirement would apply to drugs
classified as "new molecular entities" and biological products
that either (a) represent a significant therapeutic advance or
(b) would be prescribed to children more than 100,000 times per
year.
FDA estimates that it approves 5-10 drugs and biological
products per year that would require new studies under this
rule that would not otherwise have been conducted.
(In making this estimate, FDA analyzed product approvals
between 1991 and 1995, looking at 4 factors: (1) the number
of products approved with potential use in children; (2) the
number of products that the manufacturers voluntarily
studied in children; (3) based on (1) and (2), the number of
products that were not studied in children, but should have
been; (4) of the latter category, the number that
represented a significant therapeutic advance or that were
prescribed to children more than 100,000/year.)
The cost of conducting studies that adequately assess
pediatric safety and effectiveness could vary from
approximately $200,000 for a pharmacokinetic comparison of
adults and children to $3-5,000,000 for a full-scale
clinical trial.
The cost of a study is calculated based on a rough
estimate of $5,000 per subject enrolled in the study.
Pharmacokinetic studies require very few patients (40-
50, in most cases), while controlled clinical trials
may require several hundred patients.
It is difficult to estimate in advance which kinds of
studies will be needed for specific future drugs. The total
cost to manufacturers per year is therefore likely to be
between $2,000,000 and $25,000,000.
FAREWELL MEETING WITH DAVID KESSLER
February 27, 1997
DATE:
Friday, February 28, 1997
LOCATION:
Diplomatic Room
TIME:
12:00-12:30 p.m.
FROM:
Pauline Abernathy
I.
PURPOSE
To say farewell to David Kessler on his last day as FDA commissioner.
II.
BACKGROUND
Kessler asked for a few minutes with you. While the purpose of this meeting is to say
farewell, the subject of pediatric drug labeling may come up. Kessler sees failure to make
significant progress in getting pediatric safety and dosing information on more drugs with
pediatric applications as one of his greatest disappointments. In addition, on Tuesday you
will be speaking to the Pediatric AIDS Foundation, which supports FDA's issuing a
regulation requiring drug companies to provide pediatric safety and dosing information. The
Foundation also supports legislation providing financial incentives (patent-like protection) to
companies to do this, but would agree that such an approach is less desirable because it is
not well targeted. Patent-like protection would provide financial windfalls to some
companies who might have provided pediatric data anyway at very little cost.
I have been meeting with FDA and White House staff on this issue. Greg Simon gave
Kessler the green light to draft a regulatory proposal with HHS that could then be discussed
with the industry. FDA is still working on their proposal, but attached is a description of the
problem and their draft proposal. Preliminary FDA estimates suggest their proposal would
require new studies for 5-10 drugs each year, costing $200,000 to $5 million per drug.
Kessler just met with Secretary Shalala this week on this issue. Some people within the
Administration reportedly would prefer to handle this issue as part of our FDA reform
legislative proposal rather than moving forward with a rule. However, it is unclear how
quickly or slowly FDA reform will proceed, and pediatric drug labeling could be handled
administratively as we have done with tobacco. While drug companies would not support
new regulations, it would be difficult for them to oppose publicly a well-designed and
targeted rule on this subject.
III.
CLOSED PRESS
IV.
ATTACHMENTS
-FDA internal description of the issue and their draft proposal.
-Article listing the top 10 drugs prescribed for children without pediatric labeling
THE WHITE HOUSE
WASHINGTON
January 14, 1997
Susan DeLaurentis
Chief Executive Officer and Co-founder
Pediatric AIDS Foundation
1311 Colorado Avenue
Santa Monica, CA 90404
Dear Susan:
Thank you for sending me the information and proposal for Administration action to
increase children's access to safe and effective prescription drugs. I continue to be
concerned that we make progress on this issue.
As you know, at the Oval Office briefing on AIDS research on December 3, the
Vice President expressed his and the President's personal commitment to developing
pediatric applications of prevention and treatment therapies. I have asked my staff to
review your proposal with our domestic policy team, and I understand White House staff
have met with representatives of the Pediatric AIDS Foundation here in Washington.
Pauline Abernathy on my staff is working on this issue while Jennifer Klein is on maternity
leave, and she would be glad to talk with you or your staff about it.
I also just received your invitation to attend and participate in your awards ceremony
on March 4, 1997. I have forwarded a copy of your invitation to my scheduling office for
consideration.
As always, thank you for the important work that you are doing.
With warm regards, I remain
Sincerely yours,
Hillary Hillary Rodham Clinton
Hope for Children with AIDS
Dear Hillary,
It's my understanding
that proposals are under
Consideration at H HS
and not moving.
& know it's Complecated,
but wouldn't it be
announce something
great if you could
at the Elizabeth Glaser
Scientist awards Ceremony
on March 4th ?
Love,
Susan
Pediatric AIDS Foundation
311 Colorado Avenue Santa Monica California 90404
117-395-9051 Pax 310-395-5149
Pediatric AIDS Foundation
February 20, 1997
Hope for Children with AIDS
BOARD OF DIRECTORS
Paul M. Glaser
First Lady Hillary Rodham Clinton
Champerson
The White House
Susan DeLaurentis
Chief Executive Officer
Washington, DC 20500
Peter Benzian
Bob Burkett
Marlene Canter
Dear Hillary,
Philip A. Pizzo, M.D.
Susan Zeegen
Lloyd S. Zeiderman
First, thank you very much for agreeing to come to our
Elizabeth Glaser
1947-1994
Elizabeth Glaser Scientist Awards. Everyone is looking
forward to seeing you, and we believe it will be a very
EXECUTIVE ADVISORY BOARD
HONORARY CO-CHAIRS
memorable evening and a fitting tribute to Elizabeth.
President and Mrs. Ronald Reagan
Mrs. William E. Brock
Now, however, I am writing about another issue, one
Alfred A. Checchi
Kathryn D. Checchi
about which I have written to you before--pediatric
Kitty Dukakis
Michael D. Eisner
research on pharmaceuticals. After several years of
Susie Field
work with HHS, we now understand that proposals to
Senator Paula Hawkins
Elton John
make significant improvement in the way FDA deals
Michael S. Ovitz
Steven Spielberg
with drugs for children are currently under serious
Jonathan M. Tisch
Alexander Vreeland
consideration at HHS. I am writing to ask that you do
Mrs. Pete Wilson
all you can to expedite the review and adoption of such
HEALTH ADVISORY BOARD
proposals and the public commitment of the
Mary G. Boland. R.N., M.S.N
Administration to them.
Yvonne J. Bryson. M.D.
Mark Feinberg. M.D. Ph D
Over the past two years, we have been quietly talking
with David Kessler and his staff to develop
Michael S. Gottlieb. M.D
improvements in pediatric drug research. While they
Margaret C. Heagarty. MD
were initially skeptical that much could be done, they
David D. Ho. M D.
now seem enthusiastically supportive of new action on
Anna Belle Kaufman, M.F.A.. M.A.
pediatric data.
Daniel V. Landers. M.D
Michael McCune. M.D. Ph.D
We have made progress. But I feel a sense of urgency
James Oleske, M.D., M.P.H.
to press now for at least three reasons. First, David is
Catherine S. Peckham. M D.
leaving and that is a unique loss. As a pediatrician
Philip A. Pizzo. M.D
himself, he knows the issue and is an articulate
Paolo Rossi M.D
spokesman and defender. Indeed, in a recent magazine
interview he said that one of his only unmet goals
Arye Rubinstein. M.D
during his time in government was solving the pediatric
Gwendolyn B. Scott. M.D
data problem.
E. Richard Stiehm, MD
Lori Wiener, Ph.D A.C.S.W
Bernard Fields, M.D.
CO-FOUNDERS: Susan Delaurentis/Elizabeth Glaser/Susan Zeegen
1311 Colorado Avenue. Santa Monica, California 90404
TEL: (310) 395-9051
FAX: (310) 395-5149
Pediatric AIDS Foundation
Hope for Children with AIDS
Second, Congress is beginning to develop FDA "reform"
BOARD OF DIRECTORS
bills. Without a clear Administration stance on
Paul M. Glaser
pediatric data, other approaches will be developed--
creen
Susan DeLaurentis
both by children's advocates and industry--and
Chief Excense Officer
positions will be taken. This will undoubtedly
Peter Benzian
complicate the Administration's ability to act
Bob Burkett
Marlene Canter
administratively later.
Philip A. Pizzo, M.D.
Susan Zeegen
Lloyd S. Zeiderman
Finally, kids need it. While a few companies have
Elizabeth Glaser
1947-1994
begun to respond to the universal call for pediatric
data, every day a new discovery for adults is
EXECUTIVE ADVISORY BOARD
announced with no research on children. Children are
HONORARY CO-CHAIRS
President and Mrs. Ronald Reagan
left out of much biomedical progress. All sick children
Mrs. William E. Brock
are "therapeutic orphans."
Alfred A. Checchi
Kathryn D. Checchi
Kitty Dukakis
Michael D. Eisner
Whatever you can do to speed up the Administration's
Susie Field
internal action and public announcement would be
Senator Paula Hawkins
Elton John
appreciated. What I fear most now is that
Michael S. Ovitz
Steven Spielberg
unintentional delay will jeopardize the progress we've
Jonathan M. Tisch
Alexander Vreeland
made. Please let me know what we can do to help.
Mrs. Pete Wilson
HEALTH ADVISORY BOARD
Mary G. Boland, R.N., M.S.N.
Warm regards Love,
Yvonne J. Bryson. M.D.
Mark Feinberg. M.D.. Ph.D.
Suxan Susan DeLaurentis
Michael S. Gottlieb, M.D.
Co-founder
Margaret C. Heagarty. M.D.
David D. Ho. M.D
Anna Belle Kaufman. M.F.A., M.A.
Daniel V. Landers. M.D.
Michael McCune, M D.. Ph.D.
James Oleske. MD., M.P.H
Catherine S. Peckham. M.D.
Philip A. Pizzo. M.D.
Paolo Rossi. M.D.
Arye Rubinstein, M.D.
Gwendolyn B Scott. M.D.
E. Richard Stiehm, M.D.
Lon Wiener Ph.D A.C.S.W
Bernard Fields. M.D.
CO-FOUNDERS Susan DeLaurentis/Elizabeth Glaser/Susan Zeegen
1311 Colorado Avenue, Santa Monica, California 90404
TEL: (310) 395-9051
FAX: (310) 395-5149
THE WHITE HOUSE
WASHINGTON
January 14, 1997
Susan DeLaurentis
Chief Executive Officer and Co-founder
Pediatric AIDS Foundation
1311 Colorado Avenue
Santa Monica, CA 90404
Dear Susan:
Thank you for sending me the information and proposal for Administration action to
increase children's access to safe and effective prescription drugs. I continue to be
concerned that we make progress on this issue.
As you know, at the Oval Office briefing on AIDS research on December 3, the
Vice President expressed his and the President's personal commitment to developing
pediatric applications of prevention and treatment therapies. I have asked my staff to
review your proposal with our domestic policy team, and I understand White House staff
have met with representatives of the Pediatric AIDS Foundation here in Washington.
Pauline Abernathy on my staff is working on this issue while Jennifer Klein is on maternity
leave, and she would be glad to talk with you or your staff about it.
I also just received your invitation to attend and participate in your awards ceremony
on March 4, 1997. I have forwarded a copy of your invitation to my scheduling office for
consideration.
As always, thank you for the important work that you are doing.
With warm regards, I remain
Sincerely yours,
Hillary Hillary Rodham Clinton
TO:
Hillary Rodham Clinton
FROM:
Pauline Abernathy
DATE:
January 13, 1997
RE:
Letter from Susan DeLaurentis, Pediatric AIDS Foundation
Attached for your signature is a revised response to Susan DeLaurentis, about which we
spoke last week. I added an acknowledgement of the attached invitation you just received
from her to attend and participate in the Pediatric AIDS Foundation's awards dinner in
Washington, D.C. on March 4, 1997.
Other White House staff and I met with lawyers for the Pediatric AIDS Foundation last
week to discuss their proposal and possible alternatives, and we will be holding a series of
meetings this month to develop quickly recommendations for action.
You asked why the lack of pediatric safety and dosing information has attracted so much
attention now. People who have followed this issue closely for some time tell me there
are several contributing factors:
The American Academy of Pediatrics has pressed this issue for decades, but
never as aggressively or effectively as the AIDS community has.
Now that we have made HIV and AIDS therapies available more quickly,
making them more readily available for children is the next logical step.
Adult success with protease inhibitors has increased the pressure for pediatric
data. This is because protease inhibitors are quite toxic and therefore many
doctors are reluctant to prescribe them for children without pediatric data.
In 1994, FDA tried to address the issue but allowing pharmaceutical
companies to extrapolate drug effectiveness for children from adult clinical
trials, permitting them to avoid conducting two sets of expensive clinical
trials. Two years later, many experts now believe that it is clear this step was
not enough and that additional action is needed to induce the pharmaceutical
companies to conduct the much less costly pediatric safety and dosing
studies.
01/29/97 17:11
ODE
IV
HFD-104
301 427 1967
NO. 406 P002/006
Pediatric Corner
Center IDs Top 10 Drugs Used Off-Label in Out-Patient Setting
By L. Miriam Pias, M.D.
The table displays the drugs that were most widely used off-
After the Final Pediatric Rule was published in December
label in the pediatric population in 1994, according to the IMS
1994, the Pediatric Use Survey Working Group of the Pediatric
database. The drugs are presented in order of frequency of
Subcommittee was formed. The group's fust charge was E
mentions per year and reflect neither the severity of the diseases
identify the drugs most widely used in pediatrics on an out-
being treated nor the adverse events reported. Also, for drugs
patient basis for which there was inadequate use information.
used to treat chronic conditions, the number of mentions may not
Results of the survey disclosed that most drugs that are
correlate well with the number of patients being treated. In the
indicated for diseases occurring in both adults and children have
chronic use of the Schedule II drug Ritalin, for example, the
very little information about pediatric use in the labeling. Some
physician is required to prescribe it with no refills under close
age groups have less information available to them than others.
surveillance (the prescribing requirements vary from state to
The population of less than 2 years of age, for instance, has
state). Thus, in this case, the number of appearances will be-
virtually no pediatric use information on drug products in
overestimated when coropared with other drugs used chronically.
several class categories. In general, drugs used to treat diseases
Nonetheless, in every case, the physician had to make a decision
like asthma, and seasonal and perennial rhinitis, so common in
to use the drug with inappropriate pediatric use information.
children, present very little information about pediati ic drug use.
Members of the Pediatric Use Survey Working Group are:
For other therapeutic areas, such as infectious diseases, the
L Miriam Pina, M.D., chairperson, Division of Pulmonary
pediatric information is. in contrast, quite good.
Drug Products, Kimberly Struble, Division of Anti-Viral Drug
The working group analyzed survey data from IMS America,
Products; Linda Hu, Division of Over the Counter Drug
Ltd., to provide estimates for pediatric use for 1994. The IMS
Products; Jonca Bull, M.D., Division of Anti-Inflammatory,
database is an ongoing pharmaceutical marketing research
Analgesic and Ophthalmologic Drug Produces; Cazimiro
survey describing drugs mentioned during patient contacts by a
Martin. Division of Over the Counter Drug Products; Frank
nationwide panel of office-based physicians randomly selected
Rosa, recently retired from the Division of Pharmacovigilance
from the American Medical Association and the American
and Epidemiology; and Charles Maynard, Division of
Osteopathic Association (more than 2,940 physicians
Pharmacovigilance and Epidemiology. The December Pike lists
representing 27 specialties).
representatives from each of the Center's review divisions who
Data collected from the panel are projected nationally by
can assist you with Pediatric Rule issues. The working group
multiplying the raw number of mentions in each stratum,
plans on publishing in-patient data in a future issue.
defined by region and specialty, by a corresponding projection
L Miriani Pina, M.D., is a visiting scientist in the Division of
factor.
Pulmonary Drug Products.
Off-Label
Prescriber's
Product
Indication(s)
Label Statement
Prescribing
Specialty
Frequency
(percentage)
Albuterol inhalation
Prevention and relief of
Safety and effectiveness
1,626,000 to children
Pediatricians (62%)
solution for
bronchospasm.
(S&E) have not been
<12 years old.
Family practitioners
nebulization (alhuterol
cstablished in children
and allergists (20%)
sulface, 0.083 mg/ml)
below 12 years of age.
Phenergan
Relief of diverse
Should not be used in
663,000 to children
Pediatricians (82%)
(promerhazine HCI)
allergic reactions.
children below 2 years
<2 years old.
of age.
Ampicillin sodium for
Infections due 10
S&F have not been
639,000 to children
Pediatricians (88%)
intravenous or
susceptible organisms.
established in infants
<12 years old.
Most common
intramuscular
and children under the
indication: perinatal
injections.
age of 12.
infections
Page 6
The Pike, January 1997
301 827 2520
R=95%
01/29/97 17:12
ODE IV HFD-104 + 301 427 1967
NO.406 P003/006
Off-Label
Prescriber's
Product
Indication(s)
Label Statement
Prescribing
Specialty
Frequency
(percentage)
Auraigan otic solution
Prompt relief of pain of
No instructions for
600,000 to children
Pediatricians (62%)
acute otitis media and
pediatric use at any age.
<16 years old.
Family practitioners
to facilitate the removal
(23%)
of excessive or impacted
cerumen.
Lotrisone cream
Topical treatment of
S&E in children below
325,000 to children
Pediatricians (51%)
(clotrimazol 1%,
particular dermal,
the age of 12 have not
<12 years old.
Family practitioners
betamethasone
fungal infections.
been established.
(24%)
dipropionate 0.05%)
Prozac (fluoxetin HCI.)
Depression and
S&E in children have
349,000 to children
Psychiatrists (81%)
pulvules and liquid
obsessive compulsive
not been established.
<16 years old.
disorders.
Note: was mentioned to
Most common
3,000 infants <1 year of
indication: depressive
age were in 1994.
disorders
Intal (cromolyn
Prophylactic agent in
For inhalation
Intal inhalation solution
Pediatricians (71%)
sodium).
the management of
(nebulization) solution,
was prescribed 109,000
bronchial asthma.
S&E below the age of 2
times to infants
have not been established.
For inhalation acrosol
<2 years of age. Intal
solution (MDI). S&E have
inhalation aerosol
not been established
(MDI). 399,000 times
below the age of 5.
to children <5 years.'
Zoloft (sertraline HCI)
Depression.
S&E have not been
248,000 for children
Psychiatrists (72%)
established in children.
<16 years.
Ritalin tablets and
Treatment of attention
S&E have not been
226,000 10 children
Pediatricians (47%)
sustained-release tablets
deficit disorders and
established in children
<6 years old.
Psychiatrists (26%)
(methylphenidate HCI)
narcolepsy.
<6 years of age.
(Schedule 11 drug)
Alupent Syrup
Bronchodilator for
Clinical trial experience
184,000 to children
Pediatricians (59%)
(mctaproterenol
bronchial asthma and
in children under the
<6 years old.
Family practitioners
sulfate).
for reversible
age of 6 is limited.
(23%)
bronchospasms.
Beclomethasone
Relief of symptoms of
S&E in children below
174,000 to children
Pediatricians (46%)
dipropionate nasal
seasonal and perennial
the age of 6 have not
<6 years old.
sprays (includes
rhinitis and for the
been established.
Beconase AQ and
prevention of recurrence of
nasal polyps following
Vancenase AQ nasal
surgical removal.
Table date permission, a IMS America, Lid., 1994.
sprays).
The Pike January 17, 1997
Page 76
R-95%
301 827 2520
01-29-97 02:49PM P003 #18
02-27-97 09:32AM FROM FDA/OMO/IO
TO 92024562878
P001/005
Office of Policy
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857
Room 14-72
Phone (301) 827-3382
Fax (301) 443-5169
Date: 2/27/97
To:
Pauline Abernathy
Fax Number:
(202)456-2878
From:
Ann Witt
Number of Pages (including cover sheet)
4
This document is intended for the use of the party whom it is addressed and may contain information that is privileged,
confidential, and protected from disclosure under applicable law. If you are not the addressee. or the person authorized to
deliver the document to the addressee, you are hereby notified that any review, disclosure, dissemination, copying, or other
action based on the content of this communication is not authorized. If you have received this document in error. please
immediately notify us by telephone at (301) 827-3382, and return it to the above address by mail. Thank you.
02-27-97 09:32AM FROM FDA/OMO/10
TO 92024562878
P002/005
NOTE TO PAULINE ABERNATHY:
Attached are two documents that you requested from Jerry Mande concerning pediatric
labeling: (1) a preliminary assessment of the economic impact of a pediatric study requirement,
and (2) an options paper.
Please feel free to call me at (301) 827-3385 if you need anything further.
Ann Juliet Witt
December 15, 1994
Paula Botstein M.D.
CDER Pediatric Plan [the PeP]
The CDER Pediatric Plan aims at focusing sponsors, and FDA, on thinking
about all drugs in the pediatric population during two time periods:
throughout a drug's development up to approval, and during marketing.
The goal is adequately supported instructions in drug labeling for health
practitioners to prescribe medicines for the pediatric population.
1. Publish new pediatric labeling regulation.
FDA will publish a new pediatric labeling regulation to increase
adequately supported pediatric information in physician labeling of
marketed drugs. Sponsors' existing obligations to provide instructions
for physicians on using drugs in the pediatric population and FDA's
existing authority to require pediatric studies are highlighted in
discussion in the FR notice. Published 12/13/94.
2. Focus attention on pediatric patients throughout drug
development.
CDER will early and repeatedly throughout clinical drug development
cause commercial sponsors and FDA staff to focus on use of drugs in
the pediatric population. The goal is to determine, for each drug, if
studies are needed in the pediatric population, which studies are
needed, when they are needed, and get them done.
For an IND with a commercial sponsor, the key opportunities for
focusing on a drug's use in the pediatric population are:
1]. Pre-IND meeting and pre-IND submission
2]. Initial IND submission
3]. IND annual report
sr,
4]. End of phase 2 meeting to discuss a drug's full development
plan and to outline further data needed for approval
5]. Presentation of IND to an FDA drug advisory
committee
6]. Pre-NDA meeting to discuss the content and format of the
NDA
7]. The NDA submission and FDA's 45 day filing meeting
8]. Presentation of NDA to an FDA drug advisory
committee
2
At each of these opportunities, as appropriate for a drug, the sponsor
will be required to submit either a brief written pediatric plan
[sponsor's pediatric plan] or other appropriate document, e.g.
Sponsor's End of Phase 2 Pediatric Plan. FDA staff will develop
methods to insure discussion of the pediatric population at meetings
about a drug's development. FDA will, as needed, revise or create
regulations and guidances to sponsors and to FDA staff.
3. Extend Offices of Drug Evaluation Pediatric Page.
CDER will extend the current Offices of Drug Evaluation pediatric
page to all NDAs: for all action letters. A pediatric page summarizing
the state of pediatric studies is now completed only for each NME [new
molecular entity] by a reviewing division when it proposes approval to
an Office of Drug Evaluation.
Target time: second quarter of 1995.
4. May refuse to file NDAs.
CDER may refuse to file NDAs which lack appropriate analyses of
safety and effectiveness data which a sponsor already has in the
pediatric population. FDA may now refuse to file NDAs which lack
appropriate analyses of safety and effectiveness data by age [or gender],
and analyses by age includes the pediatric population. CDER will
clarify its refuse-to-file policy, guidances, and regulations, as necessary,
to specify that FDA may refuse to file NDAs for drugs with recognized
potential widespread use of the product in children if the NDAs 1].
lack a sponsor pediatric plan and 2]. lack necessary pediatric data.
5. Get studies done.
CDER will work with and advise the Pediatric Pharmacology Research
Units funded by the NICHD. The PPRUs are a new resource able to
conduct clinical and pharmacokinetic studies of drugs in the pediatric
population.
6. Require NDA Pediatric Safety Evaluation.
FDA has proposed a rule which would, among other things, require an
Overall Safety Evaluation in each periodic report to an approved NDA;
this section will require critical analysis of safety information in
pediatric treatment, along with other analyses of safety information.
Published in Federal Register, 10/27/94.
3
7. NDA Periodic Pediatric Use Report.
CDER will explore the best mechanism for insuring that periodic
reports to an NDA explicitly include pediatric use of the drug. As FDA
communicates in the preamble to the new pediatric labeling regulation,
a sponsor is already required to summarize new information about
effectiveness, or safety, of a drug and to describe actions planned
because of the new information.
Periodic reports need to include information such as the extent the drug
is used in the pediatric population, the indications for which it is used,
an analysis of available effectiveness data, and changes proposed in
labeling because of this pediatric information. Also needed is an
assessment of further pediatric data needed to assure safe and effective
use of the product in the pediatric population and the sponsor's plan for
obtaining it.
Target time: fourth quarter of 1995, when final rule is promulgated.
NOPR-see above-just published in Federal Register, 10/27/94.
8. Track Phase 4 Commitments.
CDER will intensively track phase 4 pediatric clinical studies. Before
approval of a drug, a sponsor may make commitments to conduct
clinical studies in the pediatric population during phase 4 [after
marketing approval] CDER will track commitments made, submission
of protocols, performance of studies, submission of results to NDAs,
and the percentage of commitments that result in the addition of
pediatric prescribing information to drug labeling.
9. Survey Pediatric Drug Use.
CDER will obtain data on drugs used in the pediatric population. CDER
intends to develop and fund more sources of survey data on use of
marketed drugs in the pediatric population. Drugs in categories used
frequently in the pediatric population, drugs of particular therapeutic
importance or necessity, and drugs with potential safety hazards will be
initially targeted to assure that they have adequate prescribing
information in the labeling.
10. Work with Pediatric, Pharmacy and other Communities.
CDER will intensify work with pediatric and pharmacy communities.
These include the NICHD, American Academy of Pediatrics Committee
on Drugs, AAP Committee on Infectious Diseases, Pediatric Pharmacy
4
Administrative Group, ASCPT, National AIDS Task Force, and
numerous others.
FDA will work also with its drug advisory committees, and with
industry organizations.
END of PLAN
Intra-agency Efforts.
We are pleased that CBER will join CDER in many elements of this
Pediatric Plan. CDER will work with CBER, and CDRH, on initiatives
in the CDER Pediatric Plan that may be useful for biologics and devices
for the pediatric population.
Acknowledgments
Many people have contributed thought, discussion and language to the
CDER Pediatric Plan.
of
PEDIATRICS
American Academy of Pediatrics
JULY 1998
VOLUME 98
IIII
NUMBER 1
OF
PEDIATRIC
47
A
RTICLES
1
Fireworks-related Injuries to Children G. A. Smith et al
10
Capitation Adjustment for Pediatric Populations E.J. Fowler and G. F. Anderson
18
Quality of Care for Childhood Asthma C.J. Homer et al
ROCKVILLE MD 20857-0001
5600 FISHER LN
HFD-230 RM 11805
FDA MEDICAL LIBRARY
PEDIAT 270169
24
Intubation Rates and Outcome of Very Low Birth Weight Infants C. F. Poets and B. Sens
28
Emergency Department Use by Children in the United States N. Halfon et al
35
Randomized Trial of Dust Control B. P. Lanphear et al
41
Thyroid Screening for Early Discharged Infants 1. G. Saslow et al
45
Efficacy of Glucose-based Ora! Rehydration Therapy N. Gavin et al
52
Promoting Sun Awareness C.M. Thornton and D. 1. Piacquadio
CAR-RT SORT ** C000
56
Delayed Diagnosis of Injury in Pediatric Trauma R.A. Furnival et al
63
Weight Modification Efforts Reported bv Preadolescent Girls G. B. Schreiber et al
71
Effects of In Utero Substance Exposure on Infant Neurobehavior B. Napiorkowski et al
76
Prenatal Cocaine Exposure and Neurobehavioral Performance E. Z. Tronick et al
84
Prevalence of Juvenile Chronic Arthritis P. 1. Manners and D. A. Diepeveen
91
Alcohol Misuse, Adolescent Sexual Behaviors, and Risk Taking D. M. Fergusson and
MT. Lynskey
97
Tuberculin Screening Among US Schoolchildren C.R. Driver et nl
103
Xanthine Oxidase Inhibition and Oxygen Radical Injury O.D. Saugstad
001
100
01
S ECTION REPORT
108
Section on Urology: Report of the Annual Meeting, San Francisco, California, 1995
David B. Joseph
c
OMMENTARIES
115
Changing the US Polio Immunization Schedule Would Be Bad Public Health Policy
R. Indelsohn
116
Polio Vaccine Policy-Time for a Change S. L. Katz
118
Is the "Therapeutic Orphan" About to Be Adopted? C.I. Coté et al
123
Tuberculosis Skin Testing 1. R. Starke
125
If Too Much of a Good Thing Is BAD, Is Too Much of a Bad Thing BPD' C. Cassady
127
Does Supine Sleeping Cause Asymmetric Heads? C.E. Hunt and M. S. Prezwaski
E
XPERIENCE AND REASON
130
Histrocytic Necrotizing Lymphadenitis With Autoimmune Phenomena and Meningitis in a
14-Year-Old Girl / S. Debley et al
133
Cettriaxone Choledocholithiasis I M Robertson it al
135
Management of Opioid and Benzodiazepine Dependence in Intants, Children. and
Adolescents M. Yaster it al
Committee Statements-For Contents See Pages A10 and A13
Is the "Therapeutic Orphan" About
ing for many important newly approved drugs and
to Be Adopted?
the majority of old drugs contains pediatric disclaim-
ers (Table). Significant segments of the patient pop-
ulation are left without the benefit of appropriate
In this issue of Pediatrics, the Committee on Drugs
age-specific research to document a drug's safety,
(COD) has examined the continued problem of the
efficacy, or metabolic and kinetic profiles. With the
"unapproved" use of "approved" medications in pe-
absence of FDA-approved prescribing information,
diatrics.¹ This commentary will expand on the issues
the selection and dosing of these drugs is left to the
that have restricted drug research in children and
discretion of the individual physician. For the vast
describe current initiatives to facilitate and encour-
majority of indications, even in young pediatric pa-
age such research to achieve the necessary drug la-
tients, the benefits of using many of these medica-
beling to reduce unapproved uses of medications in
tions "off-label" outweigh the risks of not using
children.
them.⁷
Drugs commonly used to treat mental or physical
BACKGROUND
pain in children, (morphine, meperidine, fentanyl,
Physicians who treat infants and children fre-
midazolam, bupivacaine, and ketorolac) illustrate
quently prescribe medications that have never been
the problem. Morphine and meperidine are com-
approved by the Food and Drug Administration
monly prescribed opioids for postoperative analge-
(FDA) for pediatric patients; unfortunately, many
sia. The package insert of one manufacturer of pa-
drugs are released without labels for pediatric use
tient-controlled analgesia (PCA) opioid formulations
and often with pediatric disclaimers. The need for
states that for morphine, "the intravenous route via
specific pediatric studies to document safety and
the
PCA infuser is not recommended for use in
efficacy before widespread exposure of children to a
individuals younger than 12 years" (Baxter mor-
new drug has been well documented.² Generally
phine sulfate injection, United States Pharmacopoeia
recognized examples of catastrophes arising from the
[USP] package insert for PCA formulation, July 1994)
lack of such studies include tetracycline-induced
The same manufacturer states that meperidine "ad-
dental dysplasia and neonatal deaths attributed to
ministered by the intravenous route via a compatible
chloramphenicol-induced "gray baby" syndrome. 3,4
infusion device is not recommended for use in indi-
From an ethical and moral perspective, children of
viduals younger than 19 years" (Baxter meperidine
all ages deserve the same proof as adults that the
hydrochloride injection, USP package insert for PCA
medications they use are safe and efficacious. How-
formulation, July 1994). Fentanyl, because of its min-
ever, most new medications and the vast majority of
imal adverse cardiovascular effects, is perhaps the
older medications have not been labeled as safe and
opioid of choice in critically ill premature and term
efficacious for pediatric use, because the research
neonates. However, the fentanyl label states that
that meets FDA standards for establishing their
"safety and efficacy in children under two years has
safety and efficacy in children has not been carried
not been established" (Janssen fentanyl citrate [Sub-
out.⁵
limaze] injection package insert, September 1992).
Clinical trial data submitted to the FDA as part of
The importance of developing age-specific drug
a New Drug Application (NDA) form the basis for
kinetic data is well recognized from many therapeu-
FDA approval and labeling of the drug. Phase I and
tic misadventures, some of which ended in patient
II premarketing clinical trials are typically limited to
death ("gray baby" syndrome with chlorampheni-
adult subjects (usually men) 20 to 40 years of age,
col).³,4 Despite these misadventures, potent drugs
followed by phase III investigations in a larger adult
used in sick children are not adequately studied. An
population, which may include the elderly. Children
excellent example is fentanyl, as described above,
are not included in the majority of premarketing
despite the knowledge that the pharmacokinetics of
clinical studies. Even when a pediatric application of
fentanyl is significantly altered by age-specific activ-
a new (or old) medication is investigated, it fre-
ity of enzymatic metabolism and neonatal hepatic
quently is carried out in a limited pediatric age
blood flow. 8-10
range, thus leaving out the majority of children. Typ-
Children also have been left out of the picture
ically, phase III is the earliest point in the clinical
with other frequently prescribed medications, such
drug development process that the FDA requests
as medications to treat asthma, seizures, psychiat-
that pediatric studies be performed.
ric disorders, and gastrointestinal motility prob-
Until recently, the FDA has not assumed a proac-
lems, sedatives, and others (Table). 2,11 One of these
tive stance to ask nor did it have the regulatory
commonly prescribed medications not labeled for
authority to force manufacturers to perform pediat-
pediatric use, cisapride (Janssen cisapride [Propul-
ric studies. Most new drugs have been labeled with
sid] package insert, January 1995), has recently
disclaimers for pediatric use." As a result, the label-
been described as causing potentially life-threaten-
ing bradycardia and prolonged QT interval in a
2-month-old infant. 12 Adenosine is now the drug of
Received for publication Mar 7. 1996; accepted Apr 4, 1996.
choice to treat pediatric supraventricular tachycar-
Reprint requests to 1.€ Department of Anesthesia, Children's Memorial
dia (S. Mithani, personal communication, Bureau
Hospital, Northwestern University Medical School, 2300 Children's Plaza,
Chicago, IL 60614
of Human Prescription Drugs Health Protection
PEDIATRICS ISSN 0031 4005). Copyright © 1996 by the American Acad-
Branch, Canada, 1996), but "no controlled studies
emy of Pediatrics
have been conducted in pediatric patients"
118
COMMENTARIES
TABLE. Drugs with Widespread use in Children and Their Pediatric Disclaimers*
Generic Name
Manufacturer's Name
Pediatric Disclaimer
Adenosine
Adenocard
No controlled studies have been conducted in
pediatric patients (Fujisawa, package insert,
May 1994)
Albuterol
Ventolin
Safety and effectiveness have not been
established in children <12 y of age for
Ventolin inhalation solution and Ventolin
nebules inhalation solution; in children <4 y
for Ventolin inhalation aerosol and Ventolin
Rotacaps for inhalation; and children <2 y for
Ventolin syrup (Glaxo, package insert, March
1995)
Bupivacaine hydrochloride
Sensorcaine
Not recommended in children <12 y due to
limited experience in controlled clinical trials
(Astra, package insert, February 1995)
Cisapride
Propulsid
Safety and effectiveness in children have not
been established (Janssen, package insert,
January 1995)
Meperidine hydrochloride
Demerol (PCA)
Not recommended for use in individuals
injection (PCA)
younger than 19 y (Baxter, package insert, July
1994)
Dobutamine
Dobutrex solution
Safety and effectiveness in children have not
been established (Lilly, package insert,
November 1993)
Dopamine
Dopamine hydrochloride injection
Safety and effectiveness in children have not
been established (American Regent, package
insert, August 1992)
Fentanyl citrate
Sublimaze
Safety and efficacy of Sublimaze in children
under 2 y has not been established (Janssen,
package insert, September 1992)
Flumazenil
Romazicon
Not recommended for use in children, as no
clinical studies have been performed to
determine risks, benefits, and dosages to be
used (Hoffmann-La Roche, package insert,
October 1994)
Fluoxetine hydrochloride
Prozac
Safety and effectiveness in children have not
been established (Lilly, package insert, March
1995)
Gabapentin
Neurontin
Safety and effectiveness in children below the
age of 12 y have not been established (Parke-
Davis, package insert, December 1994)
Ketorolac tromethamine
Toradol
Safety and efficacy in children (<16 y) have not
been established; therefore, use of Toradol in
children is not recommended (Syntex, package
insert, March 1995)
Mexiletine hvdrochloride
Mexitil
Safety and effectiveness in children have not
been established (Boehringer Ingelheim,
package insert, October 1993)
Morphine (PCA)
Morphine sulfate injection (PCA)
Not recommended for use in individuals <12 y
(Baxter, package insert, April 1994)
Midazolam hydrochloride
Versed
Safety and effectiveness of Versed in children
below the age of 18 y have not been
established (Roche, package insert, June 1994)
Nicardipine hydrochloride
Cardene
Safety and efficacy in children <18 y have not
been established (Syntex, package insert,
September 1993)
Terbutaline sulfate
Brethine
Brethine is not recommended for patients under
the age of 12 y because of insufficient clinical
data to establish safety and effectiveness (Ciba-
Geigy, package insert, August 1992)
* This table is not meant to be an all inclusive list, nor is any drug or manufacturer meant to be singled out. Data were abstracted from
package inserts. Some manufacturers may have since submitted new labeling to the Food and Drug Administration
(Fujisawa adenosine [Adenocard] intravenous
cokinetic, and pharmacodynamic data needed for
package insert, May 1994). Even older vasoactive
their safe and effective use in children. Children
medications such as dopamine (American Regent,
should not be denied the benefit of these or any
dopamine hydrochloride injection, August 1992)
medications simply because of their age. The impor-
and dobutamine (Lilly dobutamine hydrochloride
tance of developing such information cannot be
solution [Dobutrex] injection, November 1993)
overemphasized. The use of medications inade-
have pediatric disclaimers.
quately studied in children has contributed to a va-
It is a cause of deep concern that SO many medi-
riety of adverse outcomes, including seizures and
cations lack the developmental metabolic, pharma-
cardiac arrest caused by bupivacaine toxicity, pro-
COMMENTARIES
119
longed narcotic effects caused by altered hepatic
and thalidomide in 1962). 24-26 Is it true that more than
blood flow, intermediate-acting muscle relaxants be-
two decades after Shirkey's editorial, the pediatric
coming+dong+acting in neonates; benzodiazepine
patient continues to be a therapeutic orphan?
withdrawal, and interactions with antibiotics and
other sedatives. 7,8-10.13-19 These are but a few exam-
INITIATIVES TO SOLVE THE PROBLEM
ples of why pediatric pharmacologic research is im-
The COD of the American Academy of Pediatrics
portant. However, the funds needed to conduct such
(AAP) prepared a report for the FDA in 1979 that
studies are difficult to obtain, particularly for older
documented the absence of pediatric labeling for
drugs, which are no longer patented. 7,20 Most manu-
several hundred drugs used in pediatric patients. In
facturers are not interested in financing the studies
1982 the AAP COD published an additional report
necessary to develop appropriate pediatric labeling
for the FDA, "General Considerations for the Clinical
for off-patent drugs, because they have no financial
Evaluation of Drugs in Infants and Children." In
incentive to do so. Therefore, the pediatric patient is
1984 a list of 103 parenteral drugs administered to
often a "therapeutic orphan." If the necessary stud-
neonates, but without neonatal labeling, was pre-
ies are to be carried out, they likely will require
pared by the AAP COD; this was followed in 1985 by
funding from sources other than industry.
a list of the top 10 drugs widely used in neonates for
A recent example of the importance of pediatric
which there were published data (ranked according
studies is the new inhaled anesthetic agent desflu-
to use and availability of data) but that were not
rane. In preclinical studies and clinical adult trials,
labeled for pediatric use. Despite good intentions,
desflurane seemed ideal for pediatric application be-
few of these drugs subsequently have had their la-
cause of its gas partition coefficient and lack of met-
bels revised for use by infants and children.
abolic degradation. However, the pharmaceutical
The Orphan Drug Act of 1982 was primarily de-
company-supported and FDA-approved pediatric
signed to provide financial incentives to encourage
studies conducted before approval in adults found
the development of drugs with applications to small
an unexpected and unacceptably high incidence of
patient populations so that drugs with proven appli-
airway-related complications, particularly laryngo-
cability might be developed and released to a limited
spasm. 22 This observation resulted in pediatric-spe-
market (<200 patients per year). 20 However, the
cific labeling clearly stating that desflurane may be
Orphan Drug Act was not targeted specifically at
associated with airway-related complications. Seri-
pediatric patients. Although children with rare dis-
ous injury may have resulted had the appropriate
eases have benefited from the Orphan Drug Act, the
studies not been carried out in the hands of experi-
act has not stimulated or facilitated studies to obtain
enced pediatric clinical investigators. In this situa-
pediatric labeling for drugs widely used in adults.
tion, the pharmaceutical company, the FDA, and the
This failure is evidenced in part by the marked delay
academic and medical community together fulfilled
in FDA approval of zidovudine for children, because
their obligations to investigate this new drug in chil-
the appropriate pediatric studies were not carried
dren. Serious adverse effects in children and poten-
out concurrently with clinical trials in adults.
tial litigious losses would probably have resulted
In 1984, the Drug Price Competition and Patent
had the drug been released without proper pediatric
Term Restoration Act modified the process for ap-
labeling. The drug is presently recognized to be safe
proval of abbreviated NDAs, allowing more rapid
for use in children after induction and control of the
approval based on bioequivalency studies and ex-
airway.
tending patent rights to encourage studies of new
Several factors contribute to the lack of appropri-
indications for approved drugs. However, this act
ate pediatric studies: relatively small market share,
has not facilitated labeling of drugs for children.
fear of legal liability, potential long-term adverse
Despite the concerns for children voiced by the
effects, the reluctance of parents to give permission
industry through the Pharmaceutical Manufacturers
to allow their children to be research subjects, and
Association,² a survey of drug labeling in the 1990
the lack of adequate research funding from govern-
Physicians' Desk Reference revealed that for 91% of
ment, industry, and health care providers. 20 Al-
491 medications for which disclaimers or precautions
though legal liability is often an expressed concern,
against their use in children were cited, the disclaim-
the actual number of such lawsuits arising from pe-
ers or precautions were based on a lack of adequate
diatric clinical trials is negligible. 20.23 Another factor
data. Approximately 80% of new chemical entity
that has impeded pediatric clinical trials in the past is
drugs approved between 1984 and 1989 were not
that the FDA relied on the manufacturer to advise
labeled for use in children. This proportion has not
the FDA whether a drug had a pediatric indication
changed; 92 (71%) of 130 new drugs approved from
rather than independently assessing potential pedi-
1991 to 1995 did not have pediatric labeling at the
atric use.
time of approval. (At the time of this writing, com-
Shirkey, who originally coined the term "thera-
plete data for 1995 were not available.) However, at
peutic orphan,"²¹ pointed out that the lack of finan-
the request of the FDA, the manufacturers of 43
cial support by government and industry for pediat-
(33%) of these new drugs committed to or are con-
ric drug investigation is particularly ironic, because
ducting pediatric studies. The manufacturers of 49
most of the major laws that support the FDA's role in
(38%) of the new drugs told the FDA that these drugs
regulating drugs have been passed in response to
would have no pediatric indications, although at
drug-induced adverse effects occurring in the pedi-
least 21 will likelv have some pediatric use, and
atric population (ethylene glycol poisoning in 1938
another is currently one of the most commonly pre-
120
COMMENTARIES
scribed drugs for the treatment of gastroesophageal
search was the potential for litigation and ethical
reflux in children of all ages (G. Troendle, personal
problems encountered when carrying out research in
communication, 1996; Janssen cisapride [Propulsid]
children. This concern seems incongruent with the
tablets package insert, January 1995).
fact that few such lawsuits have occurred, and ethical
guidelines for drug research in children have existed
DEVELOPING SOLUTIONS
since 1977 and have been revised recently. 23,29 The
In 1988 a meeting of the AAP COD, with repre-
financial discrepancy between monetary return and
sentatives of the FDA and the pharmaceutical indus-
the investment in pediatric research required to sup-
try, was held for the purpose of discussing the issues
port pediatric studies was described. The need to
and problems associated with pediatric drug inves-
develop legislation to provide economic incentives
tigation. At the time, the role proposed for the FDA
for investigating in pediatric clinical trials was noted.
was to encourage drug companies to sponsor pedi-
The workshop highlighted eight recommendations
atric research, "if applicable," by making pediatric
to be addressed by all concerned parties in a coop-
studies a priority: (1) if a new drug had a unique
erative effort to promote and develop adequate pe-
pediatric application; or (2) if a drug would be used
diatric labeling: (1) inclusion of available pediatric
in adults but would also have an important pediatric
data in drug labeling, even if this provides only
application for the same indication. If there would be
limited pediatric information; (2) the need for a new
little therapeutic gain, but a drug may be "applica-
awareness within FDA of the importance of pediatric
ble" to pediatric patients, then "after approval" stud-
studies; (3) a de-emphasis of the need for long-term
ies would be encouraged. The concept of a "pediatric
follow-up studies unless specifically indicated; (4)
studies page" for NDAs for new molecular entities
recognition of the cost and time required to carry out
was introduced. Also, the need for incentives to the
pediatric studies; (5) the need by industry, academia,
industry to sponsor pediatric studies was discussed
and publishers of journals to provide better incen-
by representatives of the FDA familiar with the prob-
tives to conduct and publish pediatric research; (6)
lems related to drug development for children. How-
the need for the pediatric community to identify
ever, it was recognized that the FDA did not have
drugs important to the care of pediatric patients that
any legal means of compelling drug companies to
need further data in children (7) the need for the NIH
perform pediatric research, even if the drug had a
to stimulate pediatric research by providing core
recognized, important pediatric application.
funding for a recommended clinical trials network;
In April 1990 the Forum on Drug Development of
and (8) the need for the pharmaceutical industry to
the Institute of Medicine, National Academy of Sci-
consider pediatric studies at all levels of drug devel-
ences, sponsored a workshop, "Drug Development
opment. There was a consensus that the implemen-
and the Pediatric Population." This meeting was
tation of these recommendations could be achieved
convened to examine the issues that create barriers to
only by the combined effort of the industry, the
drug testing in children. Input was enlisted from the
federal government (FDA and NIH), the medical
FDA, the industry, the AAP, the National Institutes
community, and the general public.
of Health (NIH), and many pediatric pharmacolo-
gists and toxicologists. The problems cited were nu-
SOLUTIONS
merous and somewhat specific to each group of in-
It is gratifying and encouraging that several key
dividuals, depending on its perspective. 28 A plea was
recommendations from the 1990 Institute of Med-
made to the research community to develop more
icine workshop subsequently have been imple-
innovative and cost-effective research protocols with
mented. The FDA recently promulgated regulatory
better statistical designs, to avoid arbitrary age re-
changes that allow available pediatric data to be
strictions, and to develop a greater sense of commu-
included in labeling, even though the data may not
nity between parties interested in pediatric research.
meet FDA criteria for approval on the basis of
FDA representatives indicated that regulatory
safety and efficacy. If the disease for which the
changes were being explored to improve pediatric
drug is indicated is substantially the same in chil-
labeling, such as: (1) including peer-reviewed, pub-
dren as adults, efficacy in children may be extrap-
lished information on the pediatric use of drugs in
olated from adult studies. However, dose-finding
drug labeling in addition to the information from
and pharmacokinetic studies to obtain information
FDA-approved clinical trials; (2) establishing a policy
on appropriate doses and safety in children will be
of identifying the need for pediatric studies in every
required. 30 A pediatric studies page in the NDA
NDA for new molecular entities; and (3) removing
has been implemented by the FDA and is being
the FDA requirement for additional randomized and
expanded to include drugs that alreadv have ap-
double-blind efficacy studies when the disease is the
proved indications if they are being evaluated for
same in children as in adults and when information
new indications or dose formulations. The pediat-
required for infants and children is primarily for
ric studies page requires the FDA and sponsoring
dose and adverse effects rather than efficacv. The
company to identify whether pediatric studies are
need for practical endpoints for long-term follow-up
being conducted or planned and, if not, to explain
studies was also described. It was pointed out that
why. Manufacturers will be required to reexamine
support for long-term follow-up would likely need
existing information on marketed drugs to deter-
to come from government rather than industry
mine whether the labeling can be modified to in-
Representatives from the industry stated that the
clude pediatric information on the basis of adult
greatest obstacle to industry-supported drug re-
studies and available pediatric data. If so, they will
COMMENTARIES
121
be required to submit applications for supplemen-
population. The pediatric academic and private
tal labeling within 2 years. In addition, the FDA
practice communities must become more vocal in
has the authority under the new regulations to
demanding support for pediatric studies and for
request specific pediatric use information when
greater cooperation between industry, govern-
deemed necessary. Within the FDA, a special Pe-
ment, and academia to conduct the necessary stud-
diatric Subcommittee of the Medical Policy Coor-
ies when new drugs that have potential to be of
dinating Committee of the Center for Drug Evalu-
help in caring for children are introduced. There is
ation and Research, with representatives from each
a need to make the general public more aware of
division, has been formed to track the implemen-
these issues to encourage voluntary participation
tation of the new regulations and to facilitate the
in and the financial support necessary for studies
inclusion of pediatric testing in the drug develop-
in children. Children have the same medical, legal,
ment process.
and ethical rights as all other segments of the
The USP also has begun to include the latest
patient population to have clinically important
pediatric uses and drug doses in the USP Dispens-
drugs available to treat disease effectively and
ing Information based on available literature and
safely. Recent efforts by the AAP, FDA, USP, NIH,
consultation with subspecialty experts. This pro-
and Congress suggest that perhaps the drug devel-
vides a ready reference source for the practitioner,
opment and approval process is changing in a
although it does not address the lack of pediatric
positive direction for children. The recently an-
clinical trials with which official labeling can be
nounced FDA changes in regulations and the es-
supported. Nonetheless, inclusion of pediatric in-
tablishment of the Pediatric Subcommittee of the
formation will help address the reluctance of in-
Medical Policy Coordinating Committee of the
surance carriers and other third-party payers to
Center for Drug Evaluation and Research to track
pay for the use of medications that are not labeled
the implementation of new regulations regarding
for children. Because the USP Dispensing Informa-
pediatric drug testing will specifically address the
tion is one of the compendia used to document
importance of pediatric studies within each of the
accepted medication uses, this effort by the USP
FDA's 12 divisions. This should go a long way to
may help slow a reimbursement denial trend,
increasing and improving pediatric pharmacologic
which threatens the care of children.
research of new drugs and, it is hoped, in cooper-
The National Institute of Child Health and Human
ation with the pediatric pharmacology research
Development recently funded a network of pediatric
units funded by the NIH, should also address pe-
pharmacology research units expressly to carry out
diatric labeling problems for old drugs. 34 Perhaps
pediatric pharmacologic research that will support
it is also time for large purchasers of drugs, such as
pediatric labeling. The FDA is working closely with
health care systems and managed-care organiza-
the pediatric pharmacology research unit network to
tions, to apply economic pressure by basing those
conduct pediatric studies on selected therapies that
purchases in part on the presence of pediatric la-
otherwise would not be studied. 31
beling. Perhaps now, with the cooperation of the
In 1994 legislation was sponsored by Senator
industry, USP, NIH, FDA, AAP, parents, children,
Nancy Kassebaum,³² with a companion House bill
and health care providers, children no longer will
sponsored by Representative Kreidler, 33 which
be therapeutic orphans.
proposed extending the period of exclusivity of a
drug if the sponsoring company conducted pedi-
CHARLES J. COTÉ, MD
atric studies that supported labeling for children.
Department of Anesthesia
Children's Memorial Hospital
Unfortunately, this legislation was not reported
Northwestern University Medical School
out of committee. If such a bill eventually becomes
Chicago, IL 60614
law, it will provide an economic incentive to con-
RALPH E. KAUFFMAN, MD
duct pediatric studies by enhancing the opportu-
Departments of Pediatrics and Pharmacology
nity for companies to recover their investment in
Children's Mercy Hospital
pediatric studies for drugs that are necessary for
Kansas City, MO 64108
the treatment of childhood illnesses but have lim-
GLORIA J. TROENDLE, MD
ited market potential in children.
Division of Metabolic and Endocrine Drug Products
The COD of the AAP continues to work closely
Food and Drug Administration
with the FDA to foster the study and labeling of
Rockville, MD 20857
drugs for pediatric use. The committee recently sub-
GEORGE H. LAMBERT, MD
mitted a list of six drugs to the FDA that are consid-
Department of Pediatrics
ered priorities for studies in children (fentanvl, bu-
Clinical Research Center
pivacaine, midazolam, cimetidine, albuterol, and
University of Medicine and Dentistry of New Jersey
metronidazole).
Piscataway, NI 08855
It is past time that all drugs with potential pe-
diatric applications should be investigated in in-
REFERENCES
fants and children with appropriately designed
I American Academy of Pediatrics Committee on Drugs. Unapproved
industry-supported and FDA-approved studies.
uses of approved drugs: the physician. the package insert, and the Food
The unapproved or off-label use of drugs is not an
and Drug Administration: subject review. Pediatrics 1996;98:143-145
2 Workshop on Antiepileptic Drug Trials in Children. Commission on
acceptable alternative to documentation of the
antiepileptic drugs of the international league against epilepsv. Epilep-
safety and efficacy of drugs used by the pediatric
std. 1991;32.284-285
122
COMMENTARIES
3. Powell DA, Nahata MC: Chloramphenicol: new perspectives on an old
drug. Drug Intell Clin Pharm. 1982;16:295-300
Tuberculosis Skin Testing: New
4. Feder HM Jr, Osier C, Maderazo EG. Chloramphenicol: a review of its
Schools of Thought
use in clinical practice. Rev Infect Dis. 1981;3:479-491
5. Wilson JT. Pragmatic assessment of medicines available for young
children and pregnant or breast-feeding women. In: Morselli PL, Ga-
In the past 10 years, I have cared for more than 500
rattini S, Sereni F (eds): Basic and Therapeutic Aspects of Perinatal Phar.
children and adolescents with tuberculosis. Only one
macology. New York, Raven Press; 1975:411-421
6. Medical Economics Data Production Company. Physicians' Desk Refer-
of them-an asymptomatic 5-year-old with mild hi-
ence. Montvale, NJ: Medical Economics Data Production Company; 1994
lar adenopathy-was discovered via a school skin-
7. Kauffman RE Fentanyl, fads, and folly: who will adopt the therapeutic
testing program, although since 1990, the Houston
orphans? I Pediatr. 1991;119:588-589
Independent School District has required all new
8. Yaster M. The dose response of fentanyl in neonatal anesthesia. Anes-
thesiology. 1987;66:433-435
entrants to have a tuberculin skin test. During the
9. Gauntlett IS, Fisher DM, Hertzka RE, Kuhls E, Spellman MJ, Rudolph C.
last 5 years, the number of children in Houston with
Pharmacokinetics of fentanyl in neonatal humans and lambs: effects of
tuberculosis has increased. School-based skin testing
age. Anesthesiology. 1988;69:683-687
has neither found many active cases nor prevented
10. Koren G, Goresky G, Crean P, Klein J, MacLeod SM. Unexpected alter-
their occurrence.
ations in fentanyl pharmacokinetics in children undergoing cardiac
surgery: age related or disease related? Dev Pharmacol Ther. 1986;9:183-191
At first glance, requiring all schoolchildren to have
11. Psychopharmacology in children and adolescents: current problems,
a tuberculin skin test seems to be a reasonable re-
future prospects. The National Institute of Mental Health Conference;
sponse to the desire to promote prevention of a po-
January 24-25, 1995
tentially serious and still prevalent disease. This ap-
12. Lewin MB, Bryant RM, Fenrich AL, Grifka RG. Cisapride-induced long
QT interval. / Pediatr. 1996;128:279-281
proach has been championed by many well-meaning
13. Yaster M, Nichols DG, Deshpande JK, Wetzel RC. Midazolam-fentanyl
pediatricians-including myself in the past-with
intravenous sedation in children: case report of respiratory arrest. Pe-
the best of intentions. Some school boards have been
diatrics. 1990;86:463-467
convinced that skin testing of all children is an es-
14. McCloskey JJ, Haun SE, Deshpande JK. Bupivacaine toxicity secondary
sential element of tuberculosis control. The well-pub-
to continuous caudal epidural infusion in children. Anesth Analg. 1992;
75:287-290
licized resurgence of tuberculosis in the United
15. Fisher DM, Miller RD. Neuromuscular effects of vecuronium (ORG
States during the past decade has created both ap-
NC45) in infants and children during N,O halothane anesthesia. Anes-
propriate concern and unnecessary anxiety about the
thesiology. 1983;58:519-523
risk of tuberculosis in children.
16. Agarwal R, Gutlove DP, Lockhart CH. Seizures occurring in pediatric
However, within the past few years, the American
patients receiving continuous infusion of bupivacaine. Anesth Analg.
1992;75:284-286
Academy of Pediatrics (AAP), 1,2 the Centers for Dis-
17. Mevorach DL, Perkins FM, Isaacson SA. Bupivacaine toxicity secondary
ease Control and Prevention (CDC),³ and the Amer-
to continuous caudal epidural infusion in children. Anesth Analy. 1993;
ican Thoracic Society4 have stated unequivocally that
77:1305-1306
mandatory school-based tuberculin skin testing of all
18. Olkkola KT, Aranko K, Luurila H, et al. A potentially hazardous inter-
children is undesirable, an "ineffective method of
action between erythromycin and midazolam. Clin Pharmacol Ther. 1993;
53:298-305
detecting or preventing cases of childhood TB and
19 Hiller A, Olkkola KT, Isohanni P. Saarnivaara L Unconsciousness as-
should be discontinued."³ The study by Driver et al⁵
sociated with midazolam and erythromycin. Br / Annesth. 1994;65
in this issue of Pediatrics further supports this view-
826-828
point, but for different reasons.
20. Asbury CH. The Orphan Drug Act The tirst 7 years. JAMA 1991;265:
893-897
Are there potential benefits of school skin test pro-
21. Shirkev H. Editorial comment: therapeutic orphans. / Pediatr. 1968;72
grams? It is clear they are an extremely inefficient
119-120
and expensive means to find cases of tuberculosis.
22 Zwass MS, Fisher DM, Welborn LG. et al Induction and maintenance
Driver et al⁵ report that recent programs discovered
characteristics of anesthesia with destlurane and nitrous oxide in infants
tuberculosis in 0.02% or less of children tested. Pre-
and children. Anesthesiology. 1992;76:373-378
23. Yolles BJ. Litigation. Presented at the Institute of Medicine, NAS
vious investigations of childhood tuberculosis have
Workshop: Drug Development and Pediatric Populations, April 23-24,
shown that skin test screening finds few if any cas-
1990
Most children with tuberculosis are found in
24. 21 CFR $312.21(c)
one of two ways. In Houston, in about half of the
25. Kefauver-Harris Amendments; 1902. Public Law 87-781, 76 Statutes at
Large, page 780, Codified at 21 USC 301-394
children with tuberculosis, symptomatic illnesses de-
26. Snow B Drug Information: A Guide to Current Resources Chicago, II.,
velop, which are diagnosed after the children seek
Medical Library Association, Inc: 1989
medical attention. In the other half, tuberculosis is
27. Pharmaceutical Manutacturers Association. New medicines in develop-
discovered when they receive tuberculin skin tests,
ment for children. Pharmaccutical Manufacturers Association Bulletin. Fall
1990
chest radiographs, and physical examinations after
28 Institute of Medicine, Forum on Drug Development. Division of Health
exposure to an adult or adolescent with suspected or
Science Policy. Drug Development and the Pediatric Population. Report of d
proven pulmonary tuberculosis. This activity, per-
Workshop. Washington. DC National Academy Press, 1991
formed by the local public health department, is
24 Committee on Drugs. Guidelines for the ethical conduct of studies to
called a contact investigation, and it has been the
evaluate drugs in pediatric populations Pediatrics 1995;95 286-294
30 Wilson JT, Kearns GL, Murphy D, Yaffe SI. Paediatric labelling
cornerstone of finding children with recent tubercu-
requirements: implications for pharmacokinetic studies. Clin Pharmaco-
kmet. 1994:26:308-325
31. Wilson IT. Pediatric pharmacology. the path clears for a noble mission
Received for publication Mar 18, 1996. accepted Mar 27. 1940
/ Clin Pharmacol 1993,33:210-212
Dr Starke 15 supported by NIH/NHLBI grant KIF H1.03032-03.
32. Kassebaum N. Better Pharmaceuticals for Children Act of 1944. $2010
Reprint requests to (J.R.S.) Associate Professor of Pediatrics Baylor College
33. Kreidler M Better Pharmaceuticals for Children Aut of 1994. HR4427
of Medicine, I Bavlor Plaza. Houston. TX 77030
34. Department of Health and Human Services. Food and Drug Adminis-
PEDIATRICS (ISSN 0031 4005). Copyright (i) 1940 by the American Acad-
tration. Federal Register 1994-64240-64250
emy of Pediatries
COMMENTARIES
123
HHS NEWS
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
P94-21
Food and Drug Administration
FOR IMMEDIATE RELEASE
Don McLearn (301) 443-1130
Dec. 13, 1994
Home (301) 926-6909
FDA ANNOUNCES NEW RULES FOR CHILDREN'S MEDICINES
The Food and Drug Administration today announced new steps to
provide health care professionals with the information necessary to
prescribe medications more safely for children.
The new measures announced today are designed to eliminate
unnecessary risks faced by children and adolescents aged 16 and under
when treated with drugs primarily tested in adults. The vast majority
of prescription drugs currently on the market lack information about
appropriate use in children.
A key element is amending a 1979 regulation that required full
clinical trials in the pediatric population as a basis for labeling
for use in children. That rule is being amended to allow companies,
in some situations, to extrapolate from adult studies and use that
information -- along with other information about use of the drug in
children -- to provide labeling information on the appropriate use in
children.
"Taking care of our children is our top priority," said HHS
Secretary Donna E. Shalala. "These measures promise the kind of
quality medical care our children deserve."
FDA Commissioner David A. Kessler, M.D., a pediatrician,
proposed this rule change in a speech to the American
-MORE-
ATTENTION: PLEASE USE OPEN CAPTIONING FOR THE HEARING IMPAIRED.
Page 2, P94-22, Holston
In 1980, she was named deputy associate commissioner for
management and operations and held that post for six years.
In her management roles, Holston has overseen the building
of new laboratory facilities and the revision of FDA's ethics
programs to conform to the government-wide standards issued by
the Office of Government Ethics in 1992. In addition, under her
leadership, the consolidation of FDA onto a single campus was
brought from concept to implementation.
Holston has received numerous awards during her career at
FDA, including the Presidential Rank Award for Meritorious
Executives in 1992, the Commissioner's Special Citation in 1985,
1989, 1992 and 1994 and the Department of Health and Human
Services Senior Management Citation in 1988.
A native of Cleveland, Ohio, Holston received a bachelor's
degree from Barnard College, Columbia University, and a master of
public administration from the John F. Kennedy School of
Government, Harvard University.
FDA is a Public Health Service agency in HHS.
####
21
Page 2, P94-21, Pediatric Labeling
Academy of Pediatrics in October 1992. In addition to the final rule
change announced today, FDA's Center for Drug Evaluation and Research
is taking steps to increase the number of pediatric studies included
in submissions for new prescription medicines.
"We have a duty to our children," said Kessler. "We can get the
information we need to treat our children safely and effectively if
we think creatively and are willing to commit resources to the
challenge. "
The new rule, being announced in the Federal Register today,
revises the "Pediatric Use" subsection of prescription drugs labeling
and makes it easier, in some situations, for manufacturers to include
pediatric information on the label of their prescription products.
One of the rule's key provisions sets forth the conditions under
which the agency permits pediatric use statements based on adequate
and well-controlled studies in adults together with other
information, such as pharmacokinetic and safety data, that supports
pediatric use.
The rule makes clear that such pediatric use statements can be
made only if the course of the disease and the drug's effects are
sufficiently similar in the pediatric and adult populations to permit
extrapolation from the adult data to pediatric patients.
Under the new rule, manufacturers also must reexamine existing
information to determine whether the pediatric labeling of their
marketed products can be modified on the basis of adult studies and
-MORE-
Page 3, P94-21, Pediatric Labeling
other available data. If so, they have to submit an application for
supplemental labeling within two years.
Finally, the new regulation clarifies that the agency has the
authority to request specific pediatric use information. For
example, FDA may decide to request pediatric use data for a drug that
is widely used, represents a safety hazard or is therapeutically
important in the pediatric population. The rule, however, does not
limit the manner in which a practitioner may prescribe an approved
drug.
The additional measures will include the establishment of a
special pediatric subcommittee that will track the implementation of
the new regulations and draft policies and guidance documents to
ensure that the possibility of pediatric testing and use are explored
during the development of new drugs.
The agency also will work closely with the Pediatric
Pharmacology Research Units that are funded by the National Institute
of Child Health and Human Development to conduct pediatric studies on
selected therapies. Finally, FDA will work with sponsors on
investigational new drug applications and on new marketing
applications to ensure that necessary pediatric data are included for
products that have a potentially widespread use in children.
FDA is one of the Public Health Service agencies within HHS.
####
24
Page 3, P94-21, Pediatric Labeling
other available data. If so, they have to submit an application for
supplemental labeling within two years.
Finally, the new regulation clarifies that the agency has the
authority to request specific pediatric use information. For
example, FDA may decide to request pediatric use data for a drug that
is widely used, represents a safety hazard or is therapeutically
important in the pediatric population. The rule, however, does not
limit the manner in which a practitioner may prescribe an approved
drug.
The additional measures will include the establishment of a
special pediatric subcommittee that will track the implementation of
the new regulations and draft policies and guidance documents to
ensure that the possibility of pediatric testing and use are explored
during the development of new drugs.
The agency also will work closely with the Pediatric
Pharmacology Research Units that are funded by the National Institute
of Child Health and Human Development to conduct pediatric studies on
selected therapies. Finally, FDA will work with sponsors on
investigational new drug applications and on new marketing
applications to ensure that necessary pediatric data are included for
products that have a potentially widespread use in children.
FDA is one of the Public Health Service agencies within HHS.
####
24
THE WHITE HOUSE
WASHINGTON
March 18, 1997
Sheri Saltzberg, President
David C. Harvey, Executive Director
AIDS Policy Center
918 16th Street, NW Suite 201
Washington, DC 20006
Dear Ms. Saltzberg and Mr. Harvey:
Thank you for your kind words regarding the First Lady's commitment to addressing
pediatric AIDS issues and her remarks at the Elizabeth Glaser Scientist Awards ceremony earlier
this month. We are, indeed, committed to increasing children's access to safe and effective
therapies.
In your March 10th letter, you ask about the First Lady's reference at the awards
ceremony to the steps the Administration has already taken to make it easier for companies to
tailor drugs for children. The First Lady was referring to the actions the Food and Drug
Administration took in 1994, which are described in the enclosed press release. As the First
Lady said, unfortunately, despite these steps, too many drugs still have not been tested for
children or are not in a form that children can readily take. This is a serious problem that the
Administration is committed to addressing.
Your letter also asks about the status of the report requested by Congress on expedited
AIDS clinical trials for children and pregnant women and the status of making these drugs
available to adolescents. HHS staff inform me that this report will be completed and sent to
Congress very shortly.
I hope this information is helpful. Please feel free to call me if I can be of further
assistance.
Sincerely,
Office of the First Lady
Enclosure
cc:
Melanne Verveer
John Podesta
HHS NEWS
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
P94-21
Food and Drug Administration
FOR IMMEDIATE RELEASE
Don McLearn (301) 443-1130
Dec. 13, 1994
Home (301) 926-6909
FDA ANNOUNCES NEW RULES FOR CHILDREN'S MEDICINES
The Food and Drug Administration today announced new steps to
provide health care professionals with the information necessary to
prescribe medications more safely for children.
The new measures announced today are designed to eliminate
unnecessary risks faced by children and adolescents aged 16 and under
when treated with drugs primarily tested in adults. The vast majority
of prescription drugs currently on the market lack information about
appropriate use in children.
A key element is amending a 1979 regulation that required full
clinical trials in the pediatric population as a basis for labeling
for use in children. That rule is being amended to allow companies,
in some situations, to extrapolate from adult studies and use that
information -- along with other information about use of the drug in
children -- to provide labeling information on the appropriate use in
children.
"Taking care of our children is our top priority," said HHS
Secretary Donna E. Shalala. "These measures promise the kind of
quality medical care our children deserve."
FDA Commissioner David A. Kessler, M.D., a pediatrician,
proposed this rule change in a speech to the American
-MORE-
ATTENTION: PLEASE USE OPEN CAPTIONING FOR THE HEARING IMPAIRED.
Page 2, P94-21, Pediatric Labeling
Academy of Pediatrics in October 1992. In addition to the final rule
change announced today, FDA's Center for Drug Evaluation and Research
is taking steps to increase the number of pediatric studies included
in submissions for new prescription medicines.
"We have a duty to our children," said Kessler. "We can get the
information we need to treat our children safely and effectively if
we think creatively and are willing to commit resources to the
challenge."
The new rule, being announced in the Federal Register today,
revises the "Pediatric Use" subsection of prescription drugs labeling
and makes it easier, in some situations, for manufacturers to include
pediatric information on the label of their prescription products.
One of the rule's key provisions sets forth the conditions under
which the agency permits pediatric use statements based on adequate
and well-controlled studies in adults together with other
information, such as pharmacokinetic and safety data, that supports
pediatric use.
The rule makes clear that such pediatric use statements can be
made only if the course of the disease and the drug's effects are
sufficiently similar in the pediatric and adult populations to permit
extrapolation from the adult data to pediatric patients.
Under the new rule, manufacturers also must reexamine existing
information to determine whether the pediatric labeling of their
marketed products can be modified on the basis of adult studies and
-MORE-
Page 3, P94-21, Pediatric Labeling
other available data. If so, they have to submit an application for
supplemental labeling within two years.
Finally, the new regulation clarifies that the agency has the
authority to request specific pediatric use information. For
example, FDA may decide to request pediatric use data for a drug that
is widely used, represents a safety hazard or is therapeutically
important in the pediatric population. The rule, however, does not
limit the manner in which a practitioner may prescribe an approved
drug.
The additional measures will include the establishment of a
special pediatric subcommittee that will track the implementation of
the new regulations and draft policies and guidance documents to
ensure that the possibility of pediatric testing and use are explored
during the development of new drugs.
The agency also will work closely with the Pediatric
Pharmacology Research Units that are funded by the National Institute
of Child Health and Human Development to conduct pediatric studies on
selected therapies. Finally, FDA will work with sponsors on
investigational new drug applications and on new marketing
applications to ensure that necessary pediatric data are included for
products that have a potentially widespread use in children.
FDA is one of the Public Health Service agencies within HHS.
####
24
MAR-10-97 15:10 FROM AIDS POLICY CENTER
ID:2027853579
PAGE
1/6
FAX
To
Paulive Aberhatly, offer of
Fax:
456-6244
The Fuit lady
From:
Art Hay
AIDS Policy Center
APC
For Children, Youth & Families
918 Sixteenth Street, NW, Suite #201
Washington, D.C. 20006
Phone:(202)785-3564
Fax: (202)785-3579
Number of Pages Including Cover Page
If this amount of pages does not transmit please call.
BE SURE TO MARK YOUR CALENDAR
APC ANNUAL POLICY CONFERENCE
MAY 18-20, 1997 ~ BESTHESDA, MD.!!!
Please call our office for more information about the conference!
PROM:AIDS
POLICY
CENTER
ID: 2027853579
PAGE
2/6
AP
AIDS Policy Center
For Children, Youth & Families
March 10, 1997
Hillary Rodham Clinton
The White House
1600 Pennsylvania Avenue, NW
Washington, DC 20036
Dear Mrs. Clinton:
AIDS Policy Center, and the 50,000 affected children, youth and families living
with HIV and AIDS that are served by Ryan White CARE Act Title IV care and
research projects, were honored to be represented last week at the Elizabeth
Glaser Scientist Awards ceremony sponsored by the Pediatric AIDS Foundation.
Your remarks, and those of Dr. David Ho, were truly inspiring as we continue to
face the many challenges of fighting AIDS in children, youth, and families. We
deeply appreciate your commitment to addressing pediatric AIDS issues.
AIDS Policy Center has been very involved with issues related to the testing of
new drugs and expedited approval of those drugs for children and pregnant
women. The Senate Appropriations Committee requested last fall that the
administration develop a report for Congress on the status of expedited AIDS
clinical trials for children and pregnant women, and the status of making these
drugs available to adolescents. We eagerly await the release of this report which
was due to Congress on December 31, 1996 - but has not yet been completed!
Several weeks ago, AIDS Policy Center had an excellent meeting with Vice-
President Gore's staff, The White House AIDS Policy Office, and representatives
from FDA on this very issue.
During your speech to the Pediatric AIDS Foundation, you mentioned that the
Administration has already taken steps to "tailor" the new AIDS drugs for use in
children. This is exciting news and we would like to learn more about this
development. We respectively request a clarification of this statement SO that we
may accurately inform the Title IV projects across the country about AIDS drug
developments.
We encourage you to continue to address pediatric AIDS issues and invite you to
partner directly with us -- AIDS Policy Center for Children, Youth & Families - -
as we work to fight AIDS in children, youth, women and families. Thank you for
your consideration of our request and for your dedication to AIDS issues.
Sincerely,
918 Sixteenth Street, NW
Suite 201
Washington. DC 20006
The Hay
Tel: (202) 785-3564
Fax: (202) 785-3579
Sheri Saltzberg
David C. Harvey
E-mail: [email protected]
President
Executive Director
FROM:AIDS
POLICY
CENTER
R-07 97 11:33 FROM:
ID: 2027853579
PAGE
3/6
THE WHITE HOUSE
Office of the Press Secretary
For Immediate Release
March 5, 1997
FIRST LADY HILLARY RODHAM CLINTON
REMARKS TO THE PEDIATRIC AIDS FOUNDATION
ELIZABETH GLASER SCIENTIST AWARDS
Thank you for being here for this very important occasion.
E want to thank Suzie and Suzan, and all of you who are part of the board and staff of the
Pediatric AIDS Foundation I want to thank my friend Paul for his extraordinary grace and
commitment and willingness to share his feelings and experiences with the rest of us who can only
imagine what it is like for him to be worried about whether he will be able to find the drugs that
Jake needs.
We are here to honor the life and the living legacy of Elizabeth Glaser. I'm so grateful
that Elizabeth's work has been carried on by her devoted friends and husband It is something
that gives all of us a lot of hope because what Elizabeth did when she was with us, was constantly
to inspire and provoke and ask those questions that Paul was referring to. want to congratulate
the Elizabeth Glaser Scientists. You are very fortunate to have the opportunity to receive that
award, and we are very fortunate that you are using your considerable skills and the passion we
heard from each of you on behalf of this cause. None of it would be possible without the
generosity and commitment of the supporters of the Pediatric AIDS Foundation Many of you
are here tonight and I want to thank you. Some of you have been supporters of PAF for many
many years. Some of you are new to its work, but you are making an ordinary contribution,
not only to this foundation, but through this foundation to work that will literally change and save
lives. [ hope that when we think of Elizabeth Glaser, we think of how she kept pushing the
envelope. and pushing the rest of us. We no longer can hear her voice in person but I hear it often
in my, head, and any of you who have heard it as well, I hope are still listening That voice is
being heard loudly and clearly.
Over the last four years, funding for AIDS research, prevention, and care has increased by
more than half. Support for AIDS research alone has increased by 42 percent to $1.5 billion and
we now have a powerful Office of AIDS Research at the National Institutes of Health. Funding
for the Ryan White CARE Act increased by 158 percent, while the AIDS Drug Assistance
Programs, which help low-income, uninsured people with HIV and AIDS afford much-needed
therapies, have grown three-fold.
FROM:AIDS
POLICY
CENTER
R-07 97 11:33 FROM:
ID: 2027853579
PAGE
4/6
Like anything else in life, when you put in considerable effort, you are more likely to see
results. And we have seen results from this greater commitment. For the first time since the
AIDS epidemic began in 1981, the number of AIDS deaths has dropped substantially all over the
United States. The number of reported cases of mothers transmitting the AIDS virus to their
babies fell by 27 percent between 1992 and 1995.
That is good news, but there is still so very much to be done. You've already seen and
heard from scientists who are on the front line looking for cures, vaccines, doing all they can to
understand this disease. We know that daily we are trying to strengthen our prevention and
education and treatment efforts here and around the world, and it is especially important as we
look at the good news that we have received from the Center for Disease Control here in the
United States, not to forget that 90 percent of all AIDS-cases occur in other countries, countries
that are often without any resources whatsoever to treat the disease, countries where the numbers
of those who are infected with HIV are continuing to increase almost geometrically. So we have
a lot to do here and abroad to be sure that we are able to provide lifesaving prevention
information to women and young people and other groups here in our country and all those
elsewhere who are still experiencing very high rates of infection
We also know that much of the increase in survival rates here in the United States is due
to new drug therapies. And we need to make sure that all people, but particularly all children
living with HIV- AIDS have access to these life-prolonging treatments The Administration has
already taken steps to make it easier for companies to tailor drugs for children. But,
unfortunately, too many therapies still have not been tested on children or are not in a form that
children can readily take. We cannot, children like Jake cannot wait foreve to resolve this
problem. We won't wait forever. This is a serious problem, and this Administration is
committed to addressing it. But it is very important that all of you who care about this
Foundation and about children living with HIV and AIDS, make your voices heard.
Our continued success in the fight against AIDS will depend not only on the strength and
breadth of the government's commitment to research, prevention, and treatment, but also on
strong private sector leadership and support provided by such organization as the Pediatric AIDS
Foundation and the scientists we honor tonight. One of the ways that we can honor Elizabeth is
to make sure that we are united in calling for the approval and testing of drugs that children with
HIV and AIDS require. If we do that then we will continue to move down the road that Elizabeth
started. and we have all fought.
I last saw Elizabeth at a fundraiser two months beforeishe died. Though she was in great
physical pain, she had traveled across the country to New York because she never gave up hope
that the next research dollar would yield the cure she sought for her son. that the next clinical trial
would yield the answer that could allow her to disband the Pediatric AIDS Foundation for good.
PROM:AIDS
POLICY
CENTER
R-07 97 11:33 FROM:
ID: :2027853579
PAGE
5/6
Elizabeth's life is a testament to the fact that hope can triumph over despair, that we can
all find more meaning in our own lives by helping others. Her spirit is crying out for all of us to
do that with respect to those we can reach, touch, and help. So I want to congratulate all of you
for helping to bring us to this point this evening, and I hope that not only the scientists who we
honor tonight and the other Elizabeth Glaser scientists who are toiling in their labs, working so
hard to help defeat this disease, but everyone of us. will think about how we can make the
difference in this continuing struggle. When we do so, we not only honor Elizabeth Glaser, but
we honor our connection as human beings, and we give each other the greatest gift we can- that
we care and that we remain committed to ensure that every personlis treated with the dignity and
the respect that a person deserves. Thank You.
###
POLICY
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ID 2027853579
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6/6
Talking It Over
A brave spirit survives,
helping AIDS victims
I first met Elizabeth Glaser in
stantially. Late last year, the CDC
the summer of 1992 She spoke to
also announced that the number
thousands of delegates at the
of reported cases of mothers
Democratic National Convention
transmitting HIV to their babies
and millions of Americans
fell by 27 percent between 1992
watching at home on TV. Her
and 1995.
forceful words about the urgency
There are many reasons for
of the AIDS crisis moved every-
these successes, among them in
one to silence or quiet tears. Like
novative drug therapies and ag-
everyone who heard her speak, I
gressive treatments Over the last
was touched by her passion, her
four years, funding for AIDS re-=
courage and her hope.
search, prevention and care has
A blood transfusion during the
increased by more than half.
birth of Elizabeth's daughter,
Funding for health care and other
Ariel, in 1981 infected Elizabeth
assistance to HIV/AIDS patients
with the AIDS virus. Unknow-
has more than doubled, and pro-
ingly, Elizabeth passed the virus
grams that help low-income,
to Ariel through her breast milk
uninsured people with AIDS pay
and later to her son, Jake, in the
for treatments have grown
womb. Her worst fears came true
threefold.
when she and ber husband, Paul,
I know that Elizabeth would be
watched helplessly as their
encouraged by these efforts. But
daughter succumbed to AIDS at
she would also be reminding us
age 7.
that there is still much more to
Most people would have been
do. We mustn't let up on our ef
paralyzed by so many tragedies
forts to find a cure and a vaccine.
But Elizabeth turned her per-
Until we do, we need to get more
sonal battle into a fight for the life
lifesaving prevention information
and dignity of every child and ev-
to women, African-Americans,
ery person with AIDS. She re-
young people and heterosexuals,
fused to be defeated by the prej-
groups that are still experiencing
udice, fear and isolation that
high rates of infection. And we
greet so many in her situation,
need to strengthen our prevention
but instead worked tirelessly for
and treatment efforts here and
greater understanding and
around the world, especially in
awareness. With two friends, she
developing nations, where 90 per-
began the Pediatric AIDS Foun-
cent of AIDS cases occur.
dation to support and encourage
But most immediately, we need
research into the prevention and
to make sure that the life-
treatment of childhood AIDS.
prolonging drug therapies that
And as a mother hoping to save
have already helped so many
the life of her son and the lives of
adults here in America are made
other mothers' children, she lob-
more widely available to children
bied congressmen, presidents and
and others around the world who
presidential candidates, urging
are living with HIV and AIDS.
them to work harder to find a
Too many of these drug treat-
cure for AIDS.
ments still have not been tested
Since Elizabeth's death in De-
on children or made into a form
cember 1994, I've thought of her
that children can readily take.
often. I've thought of the brave
And they still have not been dis-
woman with the big smile whom I
tributed worldwide The cost of
had the privilege of getting to
these therapies has often made it
know not just as an activist but as
prohibitive to many families both
a fellow mother and friend who
here and in developing nations,-
was exactly my age. I will always
where average citizens can barely
treasure the time we spent to-
afford the price of an aspirin
gether at her home, sipping Diet
The Pediatric AIDS Foundation
Coke and talking about our chil-
is Elizabeth Glaser's living legacy.
dren, our lives and our concerns.
It is a testament to her will and
After hearing the good news
her indomitable spirit. Her spirit
last week about our progress
lives on in the breakthroughs of
against AIDS, Elizabeth has been
the scientists who have conducted
on my mind more than ever. On
and will conduct research in her
Friday, the Centers for Disease
name. Most importantly, it lives
Control announced that for the
on in every child with HIV or
first time since the AIDS epi-
AIDS who is enjoying a happy
and healthy childhood today be-
Pediatric Drug Labeling Background Materials
CLOSE HOLD
1.
Internal FDA fact sheet on the issue and a draft FDA proposal
2.
Top 10 drugs used off label on kids (without pediatric safety and dosing information on
the label)
3.
Information on FDA's 1994 actions which have failed to encourage drug manufacturers to
voluntarily provide pediatric information on labels.
4.
Wall Street Journal article on the issue.
PROPOSAL TO ADDRESS THE LACK OF PEDIATRIC LABELING FOR DRUGS
BACKGROUND
Children suffer from most of the same diseases as adults, and, by
necessity, are treated with most of the same drugs as adults.
The majority of new drugs and biological products, however, have
not been tested in pediatric populations. As a result, product
labeling frequently fails to provide directions for safe and
effective use in children, despite widespread use. An FDA survey
of drugs prescribed during 1994 identified the 10 drugs
prescribed most frequently to children without adequate labeling.
Together, these 10 drugs were prescribed more than 5,000,000
times. Because of differences in size and ability to metabolize
drugs, children require different doses than adults and may be
subject to different adverse reactions. The absence of pediatric
labeling information thus poses a serious risk of inappropriate
dosing and unexpected adverse effects in children. It may also
result in failure to provide children with optimal treatment in
cases where physicians are reluctant to prescribe potentially
toxic drugs to children before they have undergone pediatric
testing. For example, a survey by the Pediatric AIDS Foundation
found that fewer than 10% of children with AIDS were receiving
protease inhibitors, the newest and most promising AIDS drugs.
In recent years, FDA has undertaken several initiatives to
encourage the voluntary addition of pediatric use information to
drug labels. FDA has implemented a "Pediatric Plan" designed to
focus attention on and encourage voluntary development of
pediatric data during drug development. FDA has also identified
the top 10 drugs used in children without adequate labeling
instructions, and has written the manufacturers of these drugs
requesting that they submit supplemental applications to add
pediatric use information to their drug labels. In 1994, FDA
issued a new rule that allowed pediatric use information to
appear on label on the basis of substantially less data than
before, and that required manufacturers to survey existing data
to determine whether there was sufficient information to support
pediatric use information in the drug's label.
These voluntary efforts to increase the amount of pediatric use
information in labeling have not resulted in significant gains,
particularly with respect to new drugs entering the marketplace.
A comparison of drugs approved in 1991 and 1996 showed that
approximately 47% of the drugs approved in 1991 with potential
use in children had pediatric labeling, while 37% of those
approved in 1996 with potential use in children had pediatric
labeling.
total NMEs
potential
pediatric
post-
pediatric
Year
approved
use in
labeling
approval
labeling
children
at
study
later
approval
promised
submitted
1991
26
15
7
7
1
1996
53
40
15
17
?
PROPOSAL
FDA is considering proposing new regulations to address the lack
of pediatric use information by requiring, for the first time,
that applications for certain new drug and biological products
contain pediatric data. The purpose of the proposed rule would
be to ensure that important new drugs and biological products
carry adequate pediatric labeling at the time of, or soon after,
approval. The pediatric study requirement would be limited to a
small group of new drugs and biologics: new molecular entities
(the most innovative drugs) and biological products that (1)
would provide a significant therapeutic advantage to children
suffering from the disease or (2) would be expected to be used in
a substantial proportion of children. Pediatric studies could be
deferred until after approval if FDA found that it was
appropriate to delay pediatric studies until sufficient data were
collected in adults. The requirement could also be waived
altogether under certain circumstances.
The proposed rule might also codify FDA's authority to require in
compelling circumstances that manufacturers of already marketed
drugs and biological products conduct studies to support
pediatric use labeling. The circumstances in which FDA might
require pediatric studies of a marketed drug would be: (1) where
the drug is widely used in children and the lack of adequate
labeling poses significant risks to children, or (2) where the
drug offers a significant therapeutic advantage to children but
additional information is needed to permit safe and effective
use.
The absence of workable penalties has historically hampered FDA's
ability to require pediatric studies. It is inappropriate from a
public health standpoint to prevent the marketing of a drug that
offers a clinical benefit to adults simply because the
manufacturer has failed to study the drug in another subgroup of
the population. FDA is therefore considering a different type of
penalty for failure to conduct a pediatric study. FDA would take
the manufacturer to court and obtain an injunction requiring the
2
study to be completed. Violation of the injunction would be
punishable by contempt or fines.
3
01/29/97
17:11
ODE
IV
HFD-104
301 427 1967
NO.406
P002/006
Pediatric Corner
Center IDs Top 10 Drugs Used Off-Label in Out-Patient Setting
By L. Miriam Pias, M.D.
The table displays the drugs that were most widely used off-
After the Final Pediatric Rule was published in December
label in the pediatric population in 1994, according to the IMS
1994, the Pediatric Use Survey Working Group of the Pediatric
database. The drugs are presented in order of frequency of
Subcommittee was formed. The group's first charge was W
mentions per year and reflect neither the severity of the diseases
identify the drugs most widely used in pediatrics on an out-
being treated nor the adverse events reported. Also, for drugs
patient basis for which there was Inadequate use information.
used to treat chronic conditions, the number of mentions may not
Results of the survey disclosed that most drugs that are
correlate well with the number of patients being treated. In the
indicated for discases occurring in both adults and children have
chronic use of the Schedule II drug Ritalin, for example, the
very little information about pediatric use in the labeling. Some
physician is required to prescribe it with no refills under close
age groups have less information available to them than others.
surveillance (the prescribing requirements vary from state to
The population of less than 2 years of age, for instance, has
state). Thus, in this case, the number of appearances will be-
virtually no pediatric use information on drug products in
overestimated when compared with other drugs used chronically.
several class categories. In general, drugs used to treat diseases
Nonetheless, in every case, the physician had to make a decision
like asthma, and seasonal and perennial rhinitis, so common in
to use the drug with inappropriate pediatric use information.
children, present very little information about pedian ic drug use.
Members of the Pediatric Use Survey Working Group are:
For other therapeutic areas, such as infectious diseases, the
L Miriam Pina, M.D., chairperson, Division of Pulmonary
pediatric information is. in contrast, quite good.
Drug Products, Kimberly Struble, Division of Anti-Viral Drug
The working group analyzed survey data from IMS America,
Products; Linda Hu, Division of Over the Counter Drug
Ltd., to provide estimates for pediatric use for 1994. The IMS
Products; Jonca Bull, M.D., Division of Ani-Inflammatory,
database is an ongoing pharmaceutical marketing research
Analgesic and Ophthalmologic Drug Products; Cazimiro
survey describing drugs mentioned during patient contacts by a
Martin. Division of Over the Counter Drug Products: Frank
nationwide panel of office-based physicians randomly selected
Rosa, recently retired from the Division of Pharmacovigilance
from the American Medical Association and the American
and Epidemiology; and Charles Maynard, Division of
Osteopathic Association (more than 2,940 physicians
Pharmacovigilance and Epidemiology. The December Pike lists
representing 27 specialties).
representatives from each of the Center's review divisions who
Data collected from the panel are projected nationally by
can assist you with Pediatric Rule issues. The working group
multiplying the raw number of mentions in each stratum,
plans on publishing in-patient data in a future issue.
defined by region and specialty, by a corresponding projection
L Miriam Pina, M.D., is a visiting scientist in the Division of
factor.
Pulmonary Drug Products.
Off-Label
Prescriber's
Product
Indication(s)
Label Statement
Prescribing
Specialty
Frequency
(percentage)
Albuterol inhalation
Prevention and relief of
Safety and effectiveness
1,626,000 to children
Pediatricians (62%)
solution for
bronchospasm.
(S&E) have not been
<12 years old.
Family practitioners
nebulization (athuterol
cstablished in children
and allergists (20%)
sulfate, 0.083 mg/ml)
below 12 years of age.
Phenergan
Relief of diverse
Should not be used in
663,000 to children
Pediatricians (82%)
(promerhazine HCI)
allergic reactions.
children below 2 years
<2 years old.
of age.
Ampicillin sodium for
Infections due 10
S&F have not been
639,000 to children
Pediatricians (88%)
intravenous or
susceptible organisms.
established in infants
<12 years old.
Most common
intramuscular
and children under the
indication: perinatal
injections.
age of 12.
infections
Page 6
The Pike January 17 1997
01/29/97 17:12
ODE IV HFD-104
301 427 1967
NO. 406 P003/006
Off-Label
Prescriber's
Product
Indication(s)
Label Statement
Prescribing
Specialty
Frequency
(percentage)
Auralgan otic solution
Prompt relief of pain of
No instructions for
600,000 to children
Pediatricians (62%)
acute otitis media and
pediatric use at any age.
<16 years old.
Family practitioners
to facilitate the removal
(23%)
of excessive or impacted
cerumen.
Lotrisone cream
Topical treatment of
S&E in children below
325,000 to children
Pediatricians (51%)
(clotrimazol 1%,
particular dermal,
the age of 12 have not
<12 years old.
Family practitioners
betamethasone
fungal infections.
been established.
(24%)
dipropionate 0.05%)
Prozac (fluoxetin HCL)
Depression and
S&E in children have
349,000 to children
Psychiatrists (81%)
pulvules and liquid
obsessive compulsive
not been established.
<16 years old.
disorders.
Note: was mentioned to
Most common
3,000 infants <1 year of
indication: depressive
age were in 1994.
disorders
Intal (cromolyn
Prophylactic agent in
For inhalation
Intal inhalation solution
Pediatricians (71%)
sodium).
the management of
(nebulization) solution,
was prescribed 109,000
bronchial asthma.
S&E below the age of 2
times to infants
have not been established.
For inhalation acrosol
<2 years of age. Intal
solution (MDI). S&E have
inhalation acrosol
not been established
(MDI), 399,000 times
below the age of 5.
to children <5 years.'
Zoloft (sertraline HCI)
Depression.
S&E have not been
248,000 for children
Psychiatrists (72%)
established in children.
<16 years.
Ritalin tablets and
Treatment of attention
S&E have not been
226,000 to children
Pediatricians (47%)
sustained-release tablets
deficit disorders and
established in children
<6 years old.
Psychiatrists (26%)
(methylphenidate HCI)
narcolepsy.
<6 years of age.
(Schedule 11 drug)
Alupent Syrup
Bronchodilator for
Clinical trial experience
184,000 to children
Pediatricians (59%)
(mctaproterenol
bronchial asthma and
in children under the
<6 years old.
Family practitioners
sulfate).
for reversible
age of 6 is limited.
(23%)
bronchospasms.
Beclomethasone
Relief of symptoms of
S&E in children below
174,000 to children
Pediatricians (46%)
dipropionate nasal
seasonal and perennial
the age of 6 have not
<6 years old.
sprays (includes
rhinitis and (or the
been established.
Beconase AQ and
prevention of recurrence of
nasal polyps following
Vancenzse AQ nasal
surgical removal.
Table data published with permission, 0 IMS America, Ltd., 1994.
sprays).
The Pike January 17, 1997
Page IL
R-95%
301 827
HHS NEWS
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
P94-21
Food and Drug Administration
FOR IMMEDIATE RELEASE
Don McLearn (301) 443-1130
Dec. 13, 1994
Home (301) 926-6909
FDA ANNOUNCES NEW RULES FOR CHILDREN'S MEDICINES
The Food and Drug Administration today announced new steps to
provide health care professionals with the information necessary to
prescribe medications more safely for children.
The new measures announced today are designed to eliminate
unnecessary risks faced by children and adolescents aged 16 and under
when treated with drugs primarily tested in adults. The vast majority
of prescription drugs currently on the market lack information about
appropriate use in children.
A key element is amending a 1979 regulation that required full
clinical trials in the pediatric population as a basis for labeling
for use in children. That rule is being amended to allow companies,
in some situations, to extrapolate from adult studies and use that
information -- along with other information about use of the drug in
children -- to provide labeling information on the appropriate use in
children.
"Taking care of our children is our top priority," said HHS
Secretary Donna E. Shalala. "These measures promise the kind of
quality medical care our children deserve."
FDA Commissioner David A. Kessler, M.D., a pediatrician,
proposed this rule change in a speech to the American
-MORE-
ATTENTION: PLEASE USE OPEN CAPTIONING FOR THE HEARING IMPAIRED.
Page 2, P94-21, Pediatric Labeling
Academy of Pediatrics in October 1992. In addition to the final rule
change announced today, FDA's Center for Drug Evaluation and Research
is taking steps to increase the number of pediatric studies included
in submissions for new prescription medicines.
"We have a duty to our children," said Kessler. "We can get the
information we need to treat our children safely and effectively if
we think creatively and are willing to commit resources to the
challenge."
The new rule, being announced in the Federal Register today,
revises the "Pediatric Use" subsection of prescription drugs labeling
and makes it easier, in some situations, for manufacturers to include
pediatric information on the label of their prescription products.
One of the rule's key provisions sets forth the conditions under
which the agency permits pediatric use statements based on adequate
and well-controlled studies in adults together with other
information, such as pharmacokinetic and safety data, that supports
pediatric use.
The rule makes clear that such pediatric use statements can be
made only if the course of the disease and the drug's effects are
sufficiently similar in the pediatric and adult populations to permit
extrapolation from the adult data to pediatric patients.
Under the new rule, manufacturers also must reexamine existing
information to determine whether the pediatric labeling of their
marketed products can be modified on the basis of adult studies and
-MORE-
Page 3, P94-21, Pediatric Labeling
other available data. If so, they have to submit an application for
supplemental labeling within two years.
Finally, the new regulation clarifies that the agency has the
authority to request specific pediatric use information. For
example, FDA may decide to request pediatric use data for a drug that
is widely used, represents a safety hazard or is therapeutically
important in the pediatric population. The rule, however, does not
limit the manner in which a practitioner may prescribe an approved
drug.
The additional measures will include the establishment of a
special pediatric subcommittee that will track the implementation of
the new regulations and draft policies and guidance documents to
ensure that the possibility of pediatric testing and use are explored
during the development of new drugs.
The agency also will work closely with the Pediatric
Pharmacology Research Units that are funded by the National Institute
of Child Health and Human Development to conduct pediatric studies on
selected therapies. Finally, FDA will work with sponsors on
investigational new drug applications and on new marketing
applications to ensure that necessary pediatric data are included for
products that have a potentially widespread use in children.
FDA is one of the Public Health Service agencies within HHS.
####
24
THE WALL STREET JOURNAL.
FRIDAY, NOVEMBER 15, 1996 B1
In the Line for AIDS Drugs, Children Are Last
By LAURIE MCGINLEY
of all drugs approved for use in the U.S.
Staff Reporter of THE WALL STREET JOURNAL
Mostly Out of Reach
have been tested in children and have had
The revolutionary drug therapies help-
labeling information about their pediatric
ing many adult AIDS patients are unavail-
use approved by the FDA, says Susan
BRAND NAME
MANUFACTURER
APPROVAL DATE
DeLaurentis, co-founder and chief execu-
able to most infected children.
Retrovir
Glaxo Wellcome
Adults, 1987; infants and children, 1989
tive officer of the Pediatric AIDS Founda-
None of the three protease inhibitors
prescribed for adults - Roche Holding
Videx
Bristol-Myers Squibb
Adults and children, Oct. 1991
tion, which is based in Santa Monica, Calif.
Of the nine AIDS drugs that have been
Ltd.'s Invirase. Abbott Laboratories' Nor-
Hivid
Roche Holding
Adults only, June 1992
vir and Merck & Co.'s Crixivan - has been
approved for adults over the last decade,
Zerit
Bristol-Myers Squibb
Adults only, June 1994
only three have also been approved for
Epivir
Glaxo Wellcome
Adults, children and infants, Nov. 1995
pediatric use: AZT. ddl and 3TC.
MEDICINE
Invirase*
Roche Holding
Adults only, Dec. 1995
In the case of the protease inhibitors,
tested widely in children. Lacking pediat-
critics contend that drug companies have
Norvir*
Abbott Laboratories
Adults only, March 1996
ric data, the Food and Drug Administra-
been slow to develop pediatric data be-
tion hasn't cleared the drugs for use in
Crixivan*
Merck & Co.
Adults only, March 1996
cause children make up only a small
children. While doctors can legally pre-
Viramune
Boehringer Ingelheim
Adults only, June 1996
proportion of infected individuals. Since
scribe a drug for a child without such
1981, more than 7,200 children aged 12 and
Protease inhibitors
Sources: Pediatric AIDS Foundation; Food and Drug Administration
clearance if it has been approved for use by
under have been diagnosed with AIDS in
adults. many won't do so in the case of the
is adopted, to start taking a protease
Newborns aren't getting the drugs at all.
the U.S. compared with more than 548,000
protease inhibitors because of a paucity of
inhibitor. "It just scares the hell out of me
Heightening the frustration of pediatri-
adults, according to the Centers for Dis-
information. They worry that incorrect use
that I'm going to lose him." she says. But
cians and parents is the fact that some of
ease Control and Prevention. "The atti-
of the drugs could be harmful or make it
Dr. Petru wants more information about
these trials suggest that the protease in-
tude of the drug companies is that it's not
difficult for a child to use a better, yet-to-
the drugs before she considers putting him
hibitors may be of great benefit to infected
economically feasible or profitable be-
be-developed medication.
on one of the new drugs.
children. Just last week, for example, the
cause there is a limited number of infected
"I'm frustrated," says Ann Petru, di-
Of the three protease inhibitors, Roche
National Cancer Institute reported that, in
children." asserts Dianne Donovan, a
rector of the pediatric AIDS program at
Holding's Invirase was approved for adults
a small study of children aged six months
resident of Queensbury, N.Y., who adopted
Children's Hospital Oakland in California.
last December; Abbott Laboratories' Nor-
to 14 years, Abbott's drug is safe and
two children who are HIV-positive.
"I don't have any dosing information. I
vir and Merck's Crixivan were cleared
appears to have "a significant antiviral
Abbott, in particular. comes in for
have no idea what is a safe dose or a toxic
early this year. Studies in adults showed
effect."
tough criticism. Because Norvir was Ini-
one."
that the protease inhibitors, when com-
"There is such a feeling of optimism
tially developed as a liquid, making it
One of her patients is nine-year-old
bined with existing AIDS drugs, were the
and hope among adults, but it hasn't yet
readily ingestible by infants and small
Samuel Fox of Newark, Calif. While Sam-
most potent anti-AIDS weapons yet de-
been translated into hope for children."
children, it "was the one that could have
uel appears healthy - playing soccer,
vised.
says Michael Kaiser, a New Orleans doctor
been pushed into pediatric studies at a
scrapping with his older brother - tests
Teenagers with AIDS are routinely
who works with people with AIDS.
much earlier stage," says Philip Pizzo, a
show that the amount of virus in his blood
treated with the new drugs, but only the
How did this happen?
leading AIDS researcher who is physician
is six times higher than it was in March.
sickest of the younger children or those in
The fact is that the protease inhibitors
in chief and chairman of the department of
His mother, Marilyn, wants Samuel, who
small-scale clinical trials are getting them.
are part of a larger picture: Only about 20%
Please Turn to Page B9. Column 1
Two other drug companies that are
In Line for Medicines
working on new protease inhibitors,
Agouron Pharmaceuticals Inc. and Glaxo
Used to Treat AIDS,
Wellcome PLC, plan to seek FDA approval
for use by children at the same time they
Children Come Last
seek approval for use by adults. On another
front, researchers at the University of
Massachusetts Medical Center have gotten
encouraging results in tests involving in-
Continued From Page BI
fants given a new mixture of drugs not
medicine at Children's Hospital in Boston.
including any protease inhibitor.
"But the company simply didn't push hard
no FDA Commissioner David Kessler, who
to put pediatric studies in place.
already has eased the rules on pediatric
Abbott officials vehemently deny that
drug approvals once, says more needs to be
they acted too slowly or that the small size
done to prod companies to develop pediat-
of the pediatric market has influenced
ric data. The Pediatric AIDS Foundation
their priorities. They say they have fol-
backs legislation that would give compa-
lowed the prudent course of testing the
nies an extra period of market exclusivity
drug extensively on adults first. "We go
if they develop the needed information on
through a careful process where adults,
the use of their pediatric drugs.
who can give their consent, can partici-
- As for Samuel Fox, he has begun
pate; and once we have the information
speaking out about kids' access to the
from adults, we can take it to the chil-
drugs. "He wants to do something," his
dren," says John Leonard, the head of
mother says. "He's angry right now. We're
Abbott's antiviral venture. Abbott has be-
all angry.'
gun having preliminary talks with the FDA
Says Samuel: "I want to live to be an
about adding recommended doses for chil-
adult."
dren on Norvir's label, and the company
hopes it will get the go-ahead before long.
Merck and Roche are further behind.
Merck officials say they are moving as
quickly as they can to develop a liquid
that young children can take, but have
encountered frustrating obstacles involv-
ing taste and the way the drug is absorbed
In the body. Roche is working on a powder-
like pediatric version of Invirase that can
be sprinkled into a child's milk or formula
bottle. All three protease makers say they
are proceeding quickly by historical stan-
dards; in any case, various studies involv-
ing larger numbers of children are likely to
begin later this year or early next year.
12/96
From Pediatric AIDS
Foundation
PROPOSED ACTION PLAN
During the week of December 16, the President would issue an Executive Order and
accompanying statement, directing the FDA to take immediate regulatory action to ensure
that all drugs be proven safe and effective for use by children prior to their approval by
the FDA.
The Executive Order would:
Describe the dire need for pediatric data. The Order would explain that 80% of
all drugs currently on the market have not been proven safe and effective for use
by children. The Order would explain the ramifications of this situation, namely
that (1) children are being denied life-saving therapies because physicians are
afraid to prescribe potentially toxic drugs that have not been approved for use by
children, and (2) children may be exposed to an increased risk of adverse
reactions or decreased effectiveness of the drugs prescribed because pediatricians
do not have appropriate dosage data.
Explain that FDA has the statutory authority to require pediatric data prior to
its approval of a new drug. The Order would explain that pursuant to the
approval and labeling requirements of the Food, Drug, and Cosmetic Act, the
FDA has the authority to require pediatric data.
Direct the FDA to promulgate regulations requiring, as a condition of approval
for all new drugs for which children are foreseeable users, that pharmaceutical
manufacturers submit pediatric safety data, and, as appropriate, pediatric
efficacy data.¹ The Order would direct the FDA to promulgate new regulations in
accordance with the "notice and comment" procedures of the Administrative
Procedure Act.
Direct the FDA to issue the proposed regulations as soon as possible. The
Order would direct the FDA to publish. within 90 days. new proposed regulations
for public comment.
1 In most instances. efficacy data for use by children can be extrapolated from adult
efficacy data.
The statement accompanying the Executive Order would:
Describe the urgent need for pediatric data.
Declare that drugs should be safe and effective for all foreseeable users, not just
adults.
Speak about the need to ensure that children share in and benefit from
therapeutic progress.
Dedicate this action to Elizabeth Glaser, and her work to improve child health.
(Note: December 3rd was the 2nd anniversary of Elizabeth's death from AIDS-
related complications.)
Prior to issuance of the Executive Order, David Kessler and Bill Schultz (as well as PAF
representatives) would be consulted about the wording of the Order to ensure that is on
clear legal footing.
Children, pediatricians, scientists, and advocates would be present when the President
signs the Order. Attendees could include:
Representatives from the Pediatric AIDS Foundation
Children with life-threatening illnesses, such as AIDS and cancer
Parents of children with life-threatening illnesses who have been denied needed
therapies because of the lack of pediatric data
Pediatricians and scientists who have advocated for the need for pediatric data
Pediatric AIDS Foundation and other child advocacy organizations would issue press
releases lauding the President's efforts to protect the health and safety of American
children.
12/96
PediatricAIDS
Feundation
PEDIATRIC STUDIES IN PHARMACEUTICALS URGENTLY NEEDED
THE PROBLEM
Approximately 80% of all pharmaceuticals now on the market have not been tested for safety and
effectiveness in children.
Pediatricians, pharmacists, and parents are generally forced to guess about the safety and dosing
of such drugs for children, even when the drug is the only known therapy for a serious disease.
FDA has tried to encourage drug companies to conduct pediatric studies, but generally without
success.
FDA maintains that it has no means by which to compel pediatric research.
The problem seems to be getting worse.
None of the new AIDS therapies has pediatric data, even though there is every theoretical reason
to believe that the drugs would be as effective in children as in adults. Despite drug company
promises to FDA that they would start research in children after the drug is approved for adults,
such trials have not begun, delaying pediatric use by years.
A survey of pediatric AIDS patients has shown that very few of these children are taking the new
therapies, despite access to good medical care. Surveys of similarly situated adults would show
that many are getting such drugs.
Distinct pediatric data are needed. Children are not just "little adults;" they often metabolize drugs
very differently from adults and dosages are dependent on both metabolism and size.
There are classic cases of drugs that are safe in adults being toxic--even lethal--for children.
Drug companies do not gather pediatric data for a number of possible reasons.
Children are a very small market for most drugs. Research on children will not provide the
enormous returns that research on adults will.
Drug companies sometimes believe that children are difficult to recruit for trials (although when
such trials are actually begun such problems are rare).
Drug companies sometimes believe that a side effect or bad reaction by a child in research may
slow FDA approval of the therapy for adults. (Companies also may fear that if they do pediatric
trials and their competitors do not, such an adverse reaction may put them at a competitive
disadvantage with similar companies who do not do such research.)
THE PROPOSAL
FIRST, FDA should require that all new drug applications (for drugs for which children are
foreseeable users) contain pediatric safety and dosing data as a condition for approval.
Such a requirement is supported by the law.
The Food, Drug, and Cosmetic Act requires that drugs be "safe and effective," not "safe and
effective for adults only."
The legislative history of the Act is filled with clear Congressional intent to protect children.
Such a requirement for pediatric data will not slow approval of drugs.
Pediatric safety and dosing studies can be done at the same time as adult studies on effectiveness.
Since safety and dosing are relatively brief when compared to effectiveness studies, they can be
completed long before effectiveness trials are completed and ready for submission to the FDA.
Under revised regulations (December 1994), drug companies are not required to conduct the
more time-consuming effectiveness trials in children. FDA will generally allow companies to
extrapolate adult effectiveness trials to show effectiveness in children, so long as safety and
dosing studies are done.
Safety and dosing studies are generally relatively brief (3-12 months ) and relatively small (30-
60 patients) and are, therefore, relatively inexpensive.
SECOND, FDA should require manufacturers of already-approved drugs (that are determined to be
significantly needed by children) to conduct pediatric trials over a reasonable period of phase-in or
have the drug withdrawn as mislabeled.
An immediate enforcement of a requirement of pediatric studies would be unfair and unworkable
for already approved drugs.
Such pediatric data are. nonetheless, needed, both because some doctors prescribe such drugs for
children (even without data) and because some doctors do not prescribe such drugs (because of
the lack of data).
Since effectiveness trials are generally not required for children, these trials can be relatively
small and relatively brief, and, therefore, relatively inexpensive.
EXPECTED RESPONSE
Some drug companies will protest that the requirement of pediatric data will cost them money.
But note that the requirements for safety and dosing data can be met by doing relatively brief,
small, and inexpensive studies.
And note that drug companies will be forced to argue against a pediatric data requirement
without an alternative proposal for gathering such data and with a very bad past history of
ignoring the issue.
Some drug companies and Members of Congress may propose to create quasi-patent incentives for
doing pediatric studies rather than requirements.
Such legislation was discussed in both the 103rd and 104th Congress, but with no action.
But note that such incentives are not efficient (only the biggest drugs will be tested) and are
expensive (because market exclusivity delays the advent of cheaper generic drugs).
Pediatric groups (ranging from generalities (such as the American Academy of Pediatrics) to
specialists such as the Pediatric AIDS Foundation) will actively support the new requirements.
Press interest will be high.
Prepared by the Georgetown Federal Legislation Clinic on behalf of the Pediatric AIDS Foundation
(h:\therapies)
3
02-27-97 09:32AM
FROM FDA/OMO/10
TO 92024562878.
P004/005
DRAFT
OPTIONS FOR ADDRESSING LACK OF PEDIATRIC LABELING
1.
Require manufacturers of all drugs and biological products
to conduct pediatric studies
PRO:
Would provide maximum gain in pediatric labeling
CONS:
Very costly (would cover over 150 products per year)
Would sweep in many drugs that are rarely used in
children or that provide little therapeutic benefit
Inefficient use of FDA resources needed to review
studies
Strong opposition from pharmaceutical industry on
grounds of cost, liability concerns, impracticality of
conducting studies in children, and slow-down in FDA
review of new products
2.
Require manufacturers of innovative drugs that are
therapeutically significant or widely used in children to
conduct pediatric studies
PROS:
Would provide substantial gain in pediatric labeling
for products of greatest significance to children
Far less costly than option #1 to both industry and FDA
resources (would cover about 5-10 products per year)
Support from pediatric community
CONS:
Opposition from pharmaceutical industry
For a small number of products, cost of studies may
outweigh return to company
3.
Provide financial incentives to industry to perform
pediatric studies in the form of monopoly rights (patent
extensions or statutory protection from generic competition)
PROS:
Support of pharmaceutical industry
02-27-97 09:32AM FROM FDA/OMO/IO
TO 92024562878
P005/005
Depending on language of statute, could provide
substantial gain in pediatric labeling
Would ensure that companies recoup costs of pediatric
studies
CONS:
Would require new legislation
Legislation supported by industry in last session would
have provided monopoly rights for conducting pediatric
studies regardless of whether study resulted in
improved labeling information
Exclusion of competition means significantly higher
drug costs to consumers and to government
4.
Comprehensive approach, including required studies,
financial incentives, other support from the Department of
Health and Human Services, e.g., financial or other support
for pediatric studies
PROS:
Would provide substantial gains in pediatric labeling
Likely to bring broader support than options 1-3
CONS:
Much of approach beyond FDA's authority
Would require new legislation to provide financial
incentives
Higher cost to government and consumers than option 2
Pediatric Drug Labeling Background Materials
CLOSE HOLD
1.
Internal FDA fact sheet on the issue and a draft FDA proposal
2.
Top 10 drugs used off label on kids (without pediatric safety and dosing information on
the label)
3.
Information on FDA's 1994 actions which have failed to encourage drug manufacturers to
voluntarily provide pediatric information on labels.
4.
Wall Street Journal article on the issue.
PROPOSAL TO ADDRESS THE LACK OF PEDIATRIC LABELING FOR DRUGS
BACKGROUND
Children suffer from most of the same diseases as adults, and, by
necessity, are treated with most of the same drugs as adults.
The majority of new drugs and biological products, however, have
not been tested in pediatric populations. As a result, product
labeling frequently fails to provide directions for safe and
effective use in children, despite widespread use. An FDA survey
of drugs prescribed during 1994 identified the 10 drugs
prescribed most frequently to children without adequate labeling.
Together, these 10 drugs were prescribed more than 5,000,000
times. Because of differences in size and ability to metabolize
drugs, children require different doses than adults and may be
subject to different adverse reactions. The absence of pediatric
labeling information thus poses a serious risk of inappropriate
dosing and unexpected adverse effects in children. It may also
result in failure to provide children with optimal treatment in
cases where physicians are reluctant to prescribe potentially
toxic drugs to children before they have undergone pediatric
testing. For example, a survey by the Pediatric AIDS Foundation
found that fewer than 10% of children with AIDS were receiving
protease inhibitors, the newest and most promising AIDS drugs.
In recent years, FDA has undertaken several initiatives to
encourage the voluntary addition of pediatric use information to
drug labels. FDA has implemented a "Pediatric Plan" designed to
focus attention on and encourage voluntary development of
pediatric data during drug development. FDA has also identified
the top 10 drugs used in children without adequate labeling
instructions, and has written the manufacturers of these drugs
requesting that they submit supplemental applications to add
pediatric use information to their drug labels. In 1994, FDA
issued a new rule that allowed pediatric use information to
appear on label on the basis of substantially less data than
before, and that required manufacturers to survey existing data
to determine whether there was sufficient information to support
pediatric use information in the drug's label.
These voluntary efforts to increase the amount of pediatric use
information in labeling have not resulted in significant gains,
particularly with respect to new drugs entering the marketplace.
A comparison of drugs approved in 1991 and 1996 showed that
approximately 47% of the drugs approved in 1991 with potential
use in children had pediatric labeling, while 37% of those
approved in 1996 with potential use in children had pediatric
labeling.
total NMEs
potential
pediatric
post-
pediatric
Year
approved
use in
labeling
approval
labeling
children
at
study
later
approval
promised
submitted
1991
26
15
7
7
1
1996
53
40
15
17
?
PROPOSAL
FDA is considering proposing new regulations to address the lack
of pediatric use information by requiring, for the first time,
that applications for certain new drug and biological products
contain pediatric data. The purpose of the proposed rule would
be to ensure that important new drugs and biological products
carry adequate pediatric labeling at the time of, or soon after,
approval. The pediatric study requirement would be limited to a
small group of new drugs and biologics: new molecular entities
(the most innovative drugs) and biological products that (1)
would provide a significant therapeutic advantage to children
suffering from the disease or (2) would be expected to be used in
a substantial proportion of children. Pediatric studies could be
deferred until after approval if FDA found that it was
appropriate to delay pediatric studies until sufficient data were
collected in adults. The requirement could also be waived
altogether under certain circumstances.
The proposed rule might also codify FDA's authority to require in
compelling circumstances that manufacturers of already marketed
drugs and biological products conduct studies to support
pediatric use labeling. The circumstances in which FDA might
require pediatric studies of a marketed drug would be: (1) where
the drug is widely used in children and the lack of adequate
labeling poses significant risks to children, or (2) where the
drug offers a significant therapeutic advantage to children but
additional information is needed to permit safe and effective
use.
The absence of workable penalties has historically hampered FDA's
ability to require pediatric studies. It is inappropriate from a
public health standpoint to prevent the marketing of a drug that
offers a clinical benefit to adults simply because the
manufacturer has failed to study the drug in another subgroup of
the population. FDA is therefore considering a different type of
penalty for failure to conduct a pediatric study. FDA would take
the manufacturer to court and obtain an injunction requiring the
2
study to be completed. Violation of the injunction would be
punishable by contempt or fines.
3
01/29/97
17:11
ODE
IV
HFD-104
301
427
1967
NO. P002/006
Pediatric Corner
Center IDs Top 10 Drugs Used Off-Label in Out-Patient Setting
By L. Miriam Pias, M.D.
The table displays the drugs that were most widely used off-
After the Final Pediatric Rule was published in December
label in the pediatric population in 1994, according to the IMS
1994, the Pediatric Use Survey Working Group of the Pediatric
database. The drugs are presented in order of frequency of
Subcommittee was formed. The group's first charge was w
mentions per year and reflect neither the severity of the diseases
identify the drugs most widely used in pediatrics on an out-
being treated nor the adverse events reported. Also, for drugs
patient basis for which there was inadequate use information.
used to treat chronic conditions, the number of mentions may not
Results of the survey disclosed that most drugs that are
correlate well with the number of patients being treated. In the
indicated for discases occurring in both adults and children have
chronic use of the Schedule II drug Ricalin, for example, the
very little information about pediatric use in the labeling. Some
physician is required to prescribe it with no refills under close
age groups have less information available to them than others.
surveillance (the prescribing requirements vary from state to
The population of less than 2 years of age, for instance, has
state). Thus, in this case, the number of appearances will be.
virtually no pediatric use information on drug products in
overestimated when compared with other drugs used chronically.
several class categories. In general. drugs used to treat diseases
Nonetheless, in every case, the physician had to make a decision
like asthma, and seasonal and perennial rhinitis, $0 common in
to use the drug with inappropriate pediatric use information.
children, present very little information about pedian ic drug use.
Members of the Pediatric Use Survey Working Group are:
For other therapeutic areas, such as infectious diseases, the
L Miriam Pina, M.D., chairperson, Division of Pulmonary
pediatric information is. in contrast, quite good.
Drug Products, Kimberty Struble, Division of Anti-Viral Drug
The working group analyzed survey data from IMS America,
Products; Linda Hu, Division of Over the Counter Drug
Ltd., to provide estimates for pediatric use for 1994. The IMS
Products; Jonca Bull, M.D., Division of Anti-Inflammatory,
database is an ongoing pharmaceutical marketing research
Analgesic and Ophthalmologic Drug Products: Cazimiro
survey describing drugs mentioned during patient contacts by a
Martin. Division of Over the Counter Drug Products; Frank
nationwide panel of office-based physicians randomly selected
Rosa, recently retired from the Division of Pharmacovigilance
from the American Medical Association and the American
and Epidemiology: and Charles Maynard, Division of
Osteopathic Association (more than 2,940 physicians
Pharmacovigilance and Epidemiology. The December Pike lists
representing 27 specialties).
representatives from each of the Center's review divisions who
Data collected from the panel are projected nationally by
can assist you with Pediatric Rule issues. The working group
multiplying the raw number of mentions in each stratum,
plans on publishing in-patient data in a future issue.
defined by region and specialty, by a corresponding projection
L. Miriam Pina, M.D., is a visiting scientist in the Division of
factor.
Pulmonary Drug Products.
Off-Label
Prescriber's
Product
Indication(s)
Label Statement
Prescribing
Specialty
Frequency
(percentage)
Albuterol inhalation
Prevention and relief of
Safety and effectiveness
1,626,000 to children
Pediatricians (62%)
solution for
bronchospasm.
(S&E) have not been
<12 years old.
Family practitioners
nebulization (athuterol
cstablished in children
and allergists (20%)
sulface, 0.083 mg/ml)
below 12 years of age.
Phenergan
Relief of diverse
Should not be used in
663,000 to children
Pediatricians (82%)
(promerhazine HCI)
allergic reactions.
children below 2 years
<2 years old.
of age.
Ampicillin sodium for
Infections due to
S&F have not been
639,000 to children
Pediatricians (88%)
intravenous or
susceptible organisms.
established in infants
<12 years old.
Most common
intramuscular
and children under the
indication: perinatal
injections.
age of 12.
infections
Page 6
The Pike. January 17 1997
01/29/97
17:12
ODE
IV
HFD-104
301
427
1967
NO.406 P003/006
Off-Label
Prescriber's
Product
Indication(s)
Label Statement
Prescribing
Specialty
Frequency
(percentage)
Auralgan otic solution
Prompt relief of pain of
No instructions for
600,000 to children
Pediatricians (62%)
acute otitis media and
pediatric use at any sge.
<16 years old.
Family practitioners
to facilitate the removal
(23%)
of excessive or impacted
cerumen.
oursone cream
Topical treatment of
S&E in children below
325,000 to children
Pediatricians (51%)
clotrimazol 1%,
particular dermal,
the age of 12 have not
<12 years old.
Family practitioners
etamethasone
fungal infections.
been established.
(24%)
lipropionate 0.05%)
rozac (fluoxetin HCL)
Depression and
S&E in children have
349,000 to children
Psychiatrists (81%)
ulvules and liquid
obsessive compulsive
not been established.
<16 years old.
disorders.
Note: was mentioned to
Most common
3,000 infants <1 year of
indication: depressive
age were in 1994.
disorders
tal (cromolyn
Prophylactic agent in
For inhalation
Intal inhalation solution
Pediatricians (71%)
odium).
the management of
(nebulization) solution,
was prescribed 109,000
bronchial asthma.
S&E below the age of 2
times to infants
have not been established.
For inhalation acrosol
<2 years of age. Intal
solution (MDI). S&E have
inhalation aerosol
not been established
(MDI). 399,000 times
below the age of 5.
to children <5 years.'
bloft (sertraline HCI)
Depression.
S&E have not becn
248,000 for children
Psychiatrists (72%)
established in children.
<16 years.
italin tablets and
Treatment of attention
S&E have not been
226,000 to children
Pediatricians (47%)
stained-release tablets
deficit disorders and
established in children
<6 years old.
Psychiatrists (26%)
ethylphenidate HCI)
narcolepsy.
6 years of age.
chedule Il drug)
upent Syrup
Bronchodilator for
Clinical trial experience
184,000 to children
Pediatricians (59%)
ctaproterenol
bronchial asthma and
in children under the
<6 years old.
Family practitioners
Ifate).
for reversible
age of 6 is limited.
(23%)
bronchospasms.
clomethiasone
Relief of symptoms of
S&E in children below
174,000 to children
Pediatricians (46%)
propionate nasal
seasonal and perennial
the age of 6 have not
<6 years old.
ays (includes
rhinitis and for the
been established.
conase AQ and
prevention of recurrence of
nasal polyps following
ncense AQ nasal
Table
surgical removal.
Lid.,
1994.
ays).
The Pike January 17, 1997
Page 76
.95%
HHS NEWS
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
P94-21
Food and Drug Administration
FOR IMMEDIATE RELEASE
Don McLearn (301) 443-1130
Dec. 13, 1994
Home (301) 926-6909
FDA ANNOUNCES NEW RULES FOR CHILDREN'S MEDICINES
The Food and Drug Administration today announced new steps to
provide health care professionals with the information necessary to
prescribe medications more safely for children.
The new measures announced today are designed to eliminate
unnecessary risks faced by children and adolescents aged 16 and under
when treated with drugs primarily tested in adults. The vast majority
of prescription drugs currently on the market lack information about
appropriate use in children.
A key element is amending a 1979 regulation that required full
clinical trials in the pediatric population as a basis for labeling
for use in children. That rule is being amended to allow companies,
in some situations, to extrapolate from adult studies and use that
information -- along with other information about use of the drug in
children -- to provide labeling information on the appropriate use in
children.
"Taking care of our children is our top priority," said HHS
Secretary Donna E. Shalala. "These measures promise the kind of
quality medical care our children deserve."
FDA Commissioner David A. Kessler, M.D., a pediatrician,
proposed this rule change in a speech to the American
-MORE-
ATTENTION: PLEASE USE OPEN CAPTIONING FOR THE HEARING IMPAIRED.
Page 2, P94-21, Pediatric Labeling
Academy of Pediatrics in October 1992. In addition to the final rule
change announced today, FDA's Center for Drug Evaluation and Research
is taking steps to increase the number of pediatric studies included
in submissions for new prescription medicines.
"We have a duty to our children," said Kessler. "We can get the
information we need to treat our children safely and effectively if
we think creatively and are willing to commit resources to the
challenge. If
The new rule, being announced in the Federal Register today,
revises the "Pediatric Use" subsection of prescription drugs labeling
and makes it easier, in some situations, for manufacturers to include
pediatric information on the label of their prescription products.
One of the rule's key provisions sets forth the conditions under
which the agency permits pediatric use statements based on adequate
and well-controlled studies in adults together with other
information, such as pharmacokinetic and safety data, that supports
pediatric use.
The rule makes clear that such pediatric use statements can be
made only if the course of the disease and the drug's effects are
sufficiently similar in the pediatric and adult populations to permit
extrapolation from the adult data to pediatric patients.
Under the new rule, manufacturers also must reexamine existing
information to determine whether the pediatric labeling of their
marketed products can be modified on the basis of adult studies and
-MORE-
Page 3, P94-21, Pediatric Labeling
other available data. If so, they have to submit an application for
supplemental labeling within two years.
Finally, the new regulation clarifies that the agency has the
authority to request specific pediatric use information. For
example, FDA may decide to request pediatric use data for a drug that
is widely used, represents a safety hazard or is therapeutically
important in the pediatric population. The rule, however, does not
limit the manner in which a practitioner may prescribe an approved
drug.
The additional measures will include the establishment of a
special pediatric subcommittee that will track the implementation of
the new regulations and draft policies and guidance documents to
ensure that the possibility of pediatric testing and use are explored
during the development of new drugs.
The agency also will work closely with the Pediatric
Pharmacology Research Units that are funded by the National Institute
of Child Health and Human Development to conduct pediatric studies on
selected therapies. Finally, FDA will work with sponsors on
investigational new drug applications and on new marketing
applications to ensure that necessary pediatric data are included for
products that have a potentially widespread use in children.
FDA is one of the Public Health Service agencies within HHS.
####
24
THE WALL STREET JOURNAL.
FRIDAY, NOVEMBER 15, 1996 B1
In the Line for AIDS Drugs, Children Are Last
By LAURIE MCGINLEY
of all drugs approved for use in the U.S.
Staff Reporter of THE WALL. STREET JOURNAL
Mostly Out of Reach
have been tested in children and have had
The revolutionary drug therapies help-
labeling Information about their pediatric
use approved by the FDA. says Susan
ing many adult AIDS patients are unavail-
BRAND NAME
MANUFACTURER
APPROVAL DATE
DeLaurentis, co-founder and chief execu-
able to most infected children.
Retrovir
Glaxo Wellcome
Adults, 1987; infants and children, 1989
tive officer of the Pediatric AIDS Founda-
None of the three protease inhibitors
prescribed for adults - Roche Holding
Videx
Bristol-Myers Squibb
Adults and children, Oct. 1991
tion, which is based in Santa Monica, Calif.
Of the nine AIDS drugs that have been
Ltd.'s Invirase, Abbott Laboratories' Nor-
Hivid
Roche Holding
Adults only, June 1992
vir and Merck & Co.'s Crixivan - has been
approved for adults over the last decade,
Zerit
Bristol-Myers Squibb
Adults only, June 1994
only three have also been approved for
Epivir
Glaxo Wellcome
Adults, children and infants, Nov. 1995
pediatric use: AZT. ddl and 3TC.
MEDICINE
Invirase*
Roche Holding
Adults only, Dec. 1995
In the case of the protease inhibitors,
tested widely in children. Lacking pediat-
critics contend that drug companies have
Norvir*
Abbott Laboratories
Adults only, March 1996
ric data, the Food and Drug Administra-
been slow to develop pediatric data be-
tion hasn't cleared the drugs for use in
Crixivan*
Merck & Co.
Adults only, March 1996
cause children make up only a small
children. While doctors can legally pre-
Viramune
Boehringer Ingelheim
Adults only, June 1996
proportion of infected individuals. Since
scribe a drug for a child without such
1981, more than 7,200 children aged 12 and
*Protease inhibitors
Sources. Pediatric AIDS Foundation; Food and Drug Administration
clearance if it has been approved for use by
under have been diagnosed with AIDS in
adults, many won't do so in the case of the
is adopted, to start taking a protease
Newborns aren't getting the drugs at all.
the U.S. compared with more than 548,000
protease inhibitors because of a paucity of
inhibitor. "It just scares the hell out of me
Heightening the frustration of pediatri-
adults, according to the Centers for Dis-
information. They worry that incorrect use
that I'm going to lose him." she says. But
cians and parents is the fact that some of
ease Control and Prevention. "The atti-
of the drugs could be harmful or make it
Dr. Petru wants more information about
these trials suggest that the protease in-
tude of the drug companies is that it's not
difficult for a child to use a better, yet-to-
the drugs before she considers putting him
hibitors may be of great benefit to infected
economically feasible or profitable be-
be-developed medication.
on one of the new drugs.
children. Just last week, for example, the
cause there is a limited number of infected
"I'm frustrated," says Ann Petru, di-
Of the three protease inhibitors, Roche
National Cancer Institute reported that, in
children," asserts Dianne Donovan, a
rector of the pediatric AIDS program at
Holding's Invirase was approved for adults
a small study of children aged six months
resident of Queensbury, N.Y., who adopted
Children's Hospital Oakland in California.
last December: Abbott Laboratories' Nor-
to 14 years, Abbott's drug is safe and
two children who are HIV-positive.
"I don't have any dosing information. I
vir and Merck's Crixivan were cleared
appears to have "a significant antiviral
Abbott, in particular. comes in for
have no idea what is a safe dose or a toxic
early this year. Studies in adults showed
effect."
tough criticism. Because Norvir was Ini-
one."
that the protease inhibitors, when com-
"There is such a feeling of optimism
tially developed as a liquid, making it
One of her patients is nine-year-old
bined with existing AIDS drugs, were the
and hope among adults, but it hasn't yet
readily ingestible by infants and small
Samuel Fox of Newark, Calif. While Sam-
most potent anti-AIDS weapons yet de-
been translated into hope for children."
children, it "was the one that could have
uel appears healthy - playing soccer.
vised.
says Michael Kaiser, a New Orleans doctor
been pushed into pediatric studies at a
scrapping with his older brother - tests
Teenagers with AIDS are routinely
who works with people with AIDS.
much earlier stage," says Philip Pizzo, a
show that the amount of virus in his blood
treated with the new drugs, but only the
How did this happen?
leading AIDS researcher who is physician
is six times higher than it was in March.
sickest of the younger children or those in
The fact is that the protease inhibitors
in chief and chairman of the department of
His mother, Marilyn, wants Samuel, who
small-scale clinical trials are getting them.
are part of a larger picture: Only about 20%
Please Thin to Page B9, Column 1
Two other drug companies that are
In Line for Medicines
working on new protease inhibitors,
Agouron Pharmaceuticals Inc. and Glaxo
Used to Treat AIDS,
Wellcome PLC. plan to seek FDA approval
for use by children at the same time they
Children Come Last
seek approval for use by adults. On another
(ront, researchers at the University of
Massachusetts Medical Center have gotten
encouraging results in tests involving in-
Continued From Page BI
fants given a new mixture of drugs not
medicine at Children's Hospital in Boston.
including any protease inhibitor.
"But the company simply didn't push hard
10 FDA Commissioner David Kessler, who
to put pediatric studies in place.'
already has eased the rules on pediatric
Abbott officials vehemently deny that
drug approvals once, says more needs to be
they acted too slowly or that the small size
done to prod companies to develop pediat-
of the pediatric market has influenced
ric data. The Pediatric AIDS Foundation
their priorities. They say they have fol-
backs legislation that would give compa-
lowed the prudent course of testing the
nies an extra period of market exclusivity
drug extensively on adults first. "We go
if they develop the needed information on
through a careful process where adults,
the use of their pediatric drugs.
who can give their consent, can partici-
- As for Samuel Fox, he has begun
pate: and once we have the information
speaking out about kids' access to the
from adults. we can take it to the chil-
drugs. "He wants to do something." his
dren," says John Leonard, the head of
mother says. "He's angry right now. We're
Abbott's antiviral venture. Abbott has be-
all angry."
gun having preliminary talks with the FDA
Says Samuel: "I want to live to be an
about adding recommended doses for chil-
adult."
dren on Norvir's label, and the company
hopes it will get the go-ahead before long.
Merck and Roche are further behind.
Merck officials say they are moving as
quickly as they can to develop a liquid
that young children can take, but have
encountered frustrating obstacles involv-
ing taste and the way the drug is absorbed
in the body. Roche is working on a powder-
like pediatric version of Invirase that can
be sprinkled into a child's milk or formula
bottle. All three protease makers say they
are proceeding quickly by historical stan-
Hards; in any case, various studies involv-
ing larger numbers of children are likely to
begin later this year or early next year.
was w/ Waxman
Tin Insted peniatric Friends AIDS
Westmorclarl-
FDA-pediatric -
drugs
Cos. required to test
I
PHOTOCOPY
HRC HANDWRITING
TO:
Hillary Rodham Clinton
FROM:
Pauline Abernathy
DATE:
December 30, 1996
RE:
Letter from Susan DeLaurentis, Pediatric AIDS Foundation
Attached are a letter and packet of materials from the Susan DeLaurentis of the Pediatric
AIDS Foundation and a draft interim response from you. Also attached is Susan's
Christmas card to you in case you want to add a note about it.
Her letter recommends that the Administration issue an executive order directing the FDA
to require drug companies to submit pediatric safety data, and if appropriate pediatric
efficacy data, for drugs for which children are foreseeable users. I have sent copies of their
proposal to the appropriate staff in the Vice President's office and at the DPC for further
discussion when people return after the holidays.
The public-private collaborative on HIV research continues to work on this issue, and the
FDA has been informally pushing pharmaceutical companies to submit pediatric data with
certain new drug applications.
I will keep you apprised.
cc: Melanne Verveer
Pauline,
Before D send this letter,
Can you explain to me what
the problems are with changing
the regulations as furn Augusts
please Care me. Thanks,
form
THE WHITE HOUSE
WASHINGTON
January 6, 1997
Susan DeLaurentis
PHOTOCOPY
Chief Executive Officer and Co-founder
HRC HANDWRITING
Pediatric AIDS Foundation
1311 Colorado Avenue
Santa Monica, CA 90404
Dear Susan:
Thank you for sending me the information and proposal for Administration action to
increase children's access to safe and effective prescription drugs. I continue to be
concerned that we make progress on this issue.
As you know, at the Oval Office briefing on AIDS research on December 3, the
Vice President expressed his and the President's personal commitment to developing
pediatric applications of prevention and treatment therapies. I understand the public-private
Forum for Collaborative HIV Research continues to work on this issue and to look at
additional steps to increase the number of anti-HIV therapies with pediatric indications.
I have asked my staff to review your proposal with our domestic policy team.
Pauline Abernathy on my staff is working on this issue while Jennifer Klein is on maternity
leave, and she would be glad to talk with you or Tim Westmoreland.
As always, thank you for the important work that you are doing.
With warm regards, I remain
Sincerely yours,
Hillary Rodham Clinton
WSJ1/6/97
TECHNOLOGY & HEALTH
UARY 9, 1997
First Protease Inhibitor Drug Designed
Apple Plans P(
For HIV-Infected Children Is Due Soon.
Using Systems
By RHONDA L. RUNDLE
People in an advanced stage of AIDS
Staff Reporter of THE WALL STREET JOURNAL
who have exhausted treatments with the
er,
The first protease inhibitor drug de-
approved protease inhibitors have been
From Mac, Nex
signed especially for HIV-infected children
receiving Viracept since September under
is becoming available through a govern-
an "expanded access" program. Now
ment-approved giveaway program that
Agouron plans to also give the drug free of
By LEE GOMES
drug maker Agouron Pharmaceuticals Inc.
charge to infected children aged two to 13.
Staff Reporter of THE WALL STREET JOUR
will announce today.
Both programs will end as soon as the drug
Apple Computer Inc. sought to reass
The drug, Viracept, is a member of the
is approved for sale, but Agouron says
customers and software developers 1
lager.
protease inhibitor family that, when used
patients in the program won't be cut off if
the company has no plans to jettison
in combination with some older drugs, has
they don't have insurance or funds to pay
current operating system as it moves
made the AIDS virus undetectable in the
for the drug.
ward a new system based on its rec
blood of some adults. Small preliminary
Next Software Inc. acquisition.
There were about 7,300 children under
rian
Posner,
studies among children under the age of 13
At a Macintosh trade show in
S.
suggest that Viracept has comparable ben-
age 13 with AIDS in the U.S. as of June
Francisco yesterday, Apple said that
efits in youngsters, Agouron said.
1996, according to the U.S. Centers for
the next several years it plans to purs'
Disease Control. There are as many as
Pediatricians and parents of infected
"dual operating system" strategy that
20,000 HIV-infected children nationwide,
children are increasingly frustrated that
offer machines with both its existing M
protease inhibitors have been available
according to the Pediatric AIDS Founda-
intosh operating system and its new N
Equity-
tion in Santa Monica, Calif.
to only a handful of children enrolled in
based system. Company officials would
clinical trials, despite the inhibitors'
The giveaway program is "great news"
be more specific about how long the d
proven powers. Critics have accused drug
because "I have a waiting list," said
system offer will continue.
makers of being slow to act because chil-
Andrew Wiznia, director of the pediatric
Meanwhile, Apple's stock plumm
of
the
no-load
dren make up only a small proportion of
HIV program at Bronx Lebanon Hospital
as investors reacted to Apple's annou
infected individuals.
in New York. Dr. Wiznia has treated 12
ment Friday that the company will pos
Some Pediatricians Reluctant
children with Viracept during the past
operating loss as wide as $150 million
Viracept is awaiting approval by the
three months. "This is a real good drug, it
the fiscal first quarter ended Dec. 27
U.S. Food and Drug Administration follow-
may be a great drug, we don't know. It
Nasdaq Stock Market trading yester
seems to be well tolerated by children
Apple shares fell $3.875, or 18%, to $17.
come
Fund.
ing Agouron's request last month to mar-
taking it," and "only occasionally do kids
near its 52-week low of$16.
ket the drug both as a tablet for adults and
a pediatric powder for children. Protease
say 'yukky,' he said.
Pall Cast Over Trade Show
inhibitors made by three other companies
Parents with children in the study were
Apple officials have blamed the lar
"ecstatic," Dr. Wiznia said. "We've had
are being sold now, but none is approved
than-expected quarterly loss on weak
for pediatric use. Agouron, based in San
parents come in and say it was like a
sales of its Performa home compu
RBURG
Diego, is the first company to seek ap-
lightbulb went on in the child. Within one
during the holiday season. Apple also
proval for a pediatric formulation of a
or two weeks of starting therapy, some
hinted that more layoffs are likely, rai
protease inhibitor.
children are showing dramatic changes,
-927-2874)
questions about whether the Cuper
going from apathetic to interactive."
Under FDA rules, protease inhibitors
Calif., company has turned the corne
already approved for adults can be pre-
However, clinical data on such critical
its turnaround effort. Apple's PC S
scribed for children, but some pediatri-
measures as virus levels in the blood of
continue to suffer from competition 1
FUNDS
cians have been reluctant to use them
treated children haven't been disclosed
Microsoft Corp. and Intel Corp. Whe
without scientific studies into such issues
yet. Agouron says that virus-level drops
reports its first-quarter results later
as the proper dosage.
have been equivalent to those in adults, but
month, Apple will have posted more
data on the 52 children treated to date
$900 million in red ink over five quartei
won't be available until later this month.
$11.8 billion in sales.
Child Gains Weight
Last week's surprise announcer
cast a pall on the annual MacWorld t
One mother said her six-year-old
show, which is so large a gathering of
daughter has gained three or four pounds
fans that it regularly ties up traffic a
and is more active since starting Viracept
San Francisco. Nonetheless, Apple
treatment in September. "Raven eats a
cials used the gathering to fill in son
tremendous amount of food now and her
the technical details of how they pla
energy level has improved a lot," said her
using the software from Next, W
mother, Michelle Lopez. The girl has
Apple purchased last month for an
switched to Viracept tablets, cut in two for
$400 million, as the basis for a new M:
easier swallowing, because she didn't like
tosh operating system
the taste of the powder.
Ellen Hancock, Apple's chief tecl
The pediatric formulation of Viracept is
ogy officer, said the new operating
a sandy, white powder that can be scooped
tem - code named "Rhapsody" - wil
Access
out of the bottle and mixed with milk,
some pieces of Next's system and of
formula or soft foods such as pudding.
developed in-house. She told a grot
unicate with millions
Agouron said parents and doctors seeking
Apple customers that while many exit
information about the giveaway program
Mac programs will run on the new op
e-mail
users
can call 1-800-621-7111.
ing system, software developers wr
your
pager.
Some other drug makers have had
new programs for Rhapsody will ne
use different techniques and tools
trouble formulating their protease inhibi-
tors into effective medications that chil-
they do with the current Macintosh.
Even when it begins selling macl
dren can take. Abbott Laboratories, whose
with the new operating system, Apple
Norvir drug was approved for adult use last
continue to make available its cu
March, appears to be ahead of the other
operating system, known as System?
two companies with protease inhibitors on
Hancock said. System 7 should re
the market, Merck & Co. and Roche Hold-
available for several years, she said.
ing. Abbott said it expects to soon amend
Voice Mail
Industry analysts said Apple's
its label for Norvir to include children.
strategy is designed to make sure
A
company doesn't lose customers or
ware develoners while moves town:
WSJ 1/6/97
TECHNOLOGY & HEALTH
9,
1997
First Protease Inhibitor Drug Designed
Apple Plans P(
For HIV-Infected Children Is Due Soon.
Using Systems
By RHONDA L. RUNDLE
People in an advanced stage of AIDS
Staff Reporter of THE WALL STREET JOURNAL
who have exhausted treatments with the
er,
The first protease inhibitor drug de-
approved protease inhibitors have been
From Mac, Nex
signed especially for HIV-infected children
receiving Viracept since September under
is becoming available through a govern-
an "expanded access" program. Now
ment-approved giveaway program that
Agouron plans to also give the drug free of
By LEE GOMES
drug maker Agouron Pharmaceuticals Inc.
charge to infected children aged two to 13.
Staff Reporter of THE WALL STREET JOUR
will announce today.
Both programs will end as soon as the drug
Apple Computer Inc. sought to reass
ager.
The drug, Viracept, is a member of the
is approved for sale, but Agouron says
customers and software developers 1
protease inhibitor family that, when used
patients in the program won't be cut off if
the company has no plans to jettison
in combination with some older drugs, has
they don't have insurance or funds to pay
current operating system as it moves
made the AIDS virus undetectable in the
for the drug.
ward a new system based on its re
blood of some adults. Small preliminary
Next Software Inc. acquisition.
There were about 7,300 children under
Posner,
studies among children under the age of 13
At a Macintosh trade show in
S.
suggest that Viracept has comparable ben-
age 13 with AIDS in the U.S. as of June
Francisco yesterday, Apple said that
1996, according to the U.S. Centers for
efits in youngsters, Agouron said.
the next several years it plans to purs
Disease Control. There are as many as
Pediatricians and parents of infected
"dual operating system" strategy that
20,000 HIV-infected children nationwide,
children are increasingly frustrated that
offer machines with both its existing B
protease inhibitors have been available
according to the Pediatric AIDS Founda-
intosh operating system and its new N
Equity-
tion in Santa Monica, Calif.
to only a handful of children enrolled in
based system. Company officials would
clinical trials, despite the inhibitors'
The giveaway program is "great news"
be more specific about how long the d
proven powers. Critics have accused drug
because "I have a waiting list," said
system offer will continue.
makers of being slow to act because chil-
Andrew Wiznia, director of the pediatric
Meanwhile, Apple's stock plumm
of
the
no-load
dren make up only a small proportion of
HIV program at Bronx Lebanon Hospital
as investors reacted to Apple's annou
infected individuals.
in New York. Dr. Wiznia has treated 12
ment Friday that the company will pos
Some Pediatricians Reluctant
children with Viracept during the past
operating loss as wide as $150 million
Viracept is awaiting approval by the
three months. "This is a real good drug, it
the fiscal first quarter ended. Dec. 27
U.S. Food and Drug Administration follow-
may be a great drug, we don't know. It
Nasdaq Stock Market trading yesten
seems to be well tolerated by children
Apple shares fell $3.875, or 18%, to $17.
Fund.
ing Agouron's request last month to mar-
ket the drug both as a tablet for adults and
taking it," and "only occasionally do kids
near its 52-week low of$$16.
a pediatric powder for children. Protease
say 'yukky,' he said.
Pall Cast Over Trade Show
Parents with children in the study were
inhibitors made by three other companies
Apple officials have blamed the lar
"ecstatic," Dr. Wiznia said. "We've had
are being sold now, but none is approved
than-expected quarterly loss on weak
for pediatric use. Agouron, based in San
parents come in and say it was like a
sales of its Performa home compu
JRG
lightbulb went on in the child. Within one
Diego, is the first company to seek ap-
during the holiday season. Apple a
or two weeks of starting therapy, some
proval for a pediatric formulation of a
hinted that more layoffs are likely, rai
children are showing dramatic changes,
-927-2874)
protease inhibitor.
questions about whether the Cupert
going from apathetic to interactive."
Under FDA rules, protease inhibitors
Calif., company has turned the corne
already approved for adults can be pre-
However, clinical data on such critical
its turnaround effort. Apple's PC $
scribed for children, but some pediatri-
measures as virus levels in the blood of
continue to suffer from competition f
FUNDS
cians have been reluctant to use them
treated children haven't been disclosed
Microsoft Corp. and Intel Corp. Whe
without scientific studies into such issues
yet. Agouron says that virus-level drops
reports its first-quarter results. later
as the proper dosage.
have been equivalent to those in adults, but
month, Apple will have posted more 1
data on the 52 children treated to date
$900 million in red ink over five quarter
won't be available until later this month.
$11.8 billion in sales.
Child Gains Weight
Last week's surprise announcer
cast a pall on the annual MacWorld t
One mother said her six-year-old
show, which is so large a gathering of
daughter has gained three or four pounds
fans that it regularly ties up traffic ac
and is more active since starting Viracept
San Francisco. Nonetheless, Apple
treatment in September. "Raven eats a
cials used the gathering to fill in som
tremendous amount of food now and her
the technical details of how they plan
energy level has improved a lot," said her
using the software from Next, W
mother, Michelle Lopez. The girl has
Apple purchased last month for an
switched to Viracept tablets, cut in two for
$400 million, as the basis for a new Ma
easier swallowing, because she didn't like
tosh operating system
the taste of the powder.
Ellen Hancock, Apple's chief teci
The pediatric formulation of Viracept is
ogy officer, said the new operating
a sandy, white powder that can be scooped
tem - code named "Rhapsody" - wil
Access
out of the bottle and mixed with milk,
some pieces of Next's system and ot
formula or soft foods such as pudding.
developed in-house. She told a grou
unicate
with
millions
Agouron said parents and doctors seeking
Apple customers that while many exis
information about the giveaway program
Mac programs will run on the new op
e-máil
users
can call 1-800-621-7111.
ing system, software developers wr
your
pager.
Some other drug makers have had
new programs for Rhapsody will nee
trouble formulating their protease inhibi-
use different techniques and tools
tors into effective medications that chil-
they do with the current Macintosh.
dren can take. Abbott Laboratories, whose
Even when it begins selling mach
Norvir drug was approved for adult use last
with the new operating system, Apple
March, appears to be ahead of the other
continue to make available its cur
two companies with protease inhibitors on
operating system, known as System 7,
the market, Merck & Co. and Roche Hold-
Hancock said. System 7 should res
ing. Abbott said it expects to soon amend
available for several years, she said.
Voice Mail
its label for Norvir to include children.
Industry analysts said Apple's
strategy is designed to make sure
A-toll-free voice-mail.systen
company doesn't lose customers or
12/20/96 FRI 16:58 FAX 2026321090
AIDS POLICY
004
THE WHITE HOUSE
OFFICE OF THE VICE PRESIDENT
FOR IMMEDIATE RELEASE
CONTACT: 202-456-7035
WEDNESDAY, February 21, 1996
Vice President Gore Says Meeting
With Pharmaceutical Firms,
AIDS Researchers, An Important Step
in Fight Against Disease
WASHINGTON -- Highlighting his and President Clinton's
commitment to AIDS drug development, Vice President Gore met
Tuesday (2/20) with pharmaceutical company representatives and
leading government researchers. He said the private and public
sectors should accelerate their joint effort to find and develop
as quickly as possible AIDS vaccines, therapeutics, and
microbicides.
Attending the meeting were representatives of 11
pharmaceutical companies and leading AIDS researchers and
officials from the National Institutes of Health, the Department
of Defense, and the Food and Drug Administration. They discussed
ways to accelerate the development of AIDS vaccines,
therapeutics, and microbicides.
"This meeting was an important step in strengthening the
government-industry partnership that is essential to finding and
developing effective treatments -- and ultimately a cure -- for
AIDS, BO Vice President Gore said. "We are committed to
marshalling our best minds and resources in the fight against
AIDS."
At the December 6, 1995, White House Conference on HIV and
AIDS, President Clinton asked Vice President Gore to convene this
meeting to "identify all the ways in which we might accelerate
the development of vaccines, therapeutics, and microbicides that
can protect people from HIV and the infections it causes." The
meeting reflects President Clinton's commitment to bring the AIDS
epidemic to an end.
In his three years in office, President Clinton has
increased funding for AIDS research by 26 percent, expedited AIDS
drug approval, and strengthened the Office of AIDS Research at
the National Institutes of Health.
At the conclusion of the two-hour meeting, Vice President Gore
announced the following steps:
The Administration will join with pharmaceutical
manufacturers, health insurance companies and other third-
party payers, and patient advocacy organizations to develop
12/20/96 FRI 16:57 FAX 2026321090
AIDS POLICY
002
a collaborative system of clinical trials of AIDS drugs that
have been approved by the FDA under expedited procedures to
determine the best uses and the long-term effectiveness of
those drugs.
The Administration will work with international
organizations -- such as the World Bank -- to increase
investment in AIDS vaccine development and trials worldwide.
The Administration will help facilitate the development of
microbicides to enable women to protect themselves from HIV
infection.
The Vice President will facilitate ongoing discussions
between the government and the pharmaceutical industry to
identify promising areas of AIDS research that the
government can support in order to stimulate private sector
investment in the next generation of AIDS vaccines,
therapeutics, and microbicides.
The Food and Drug Administration will pursue additional
measures to increase the number of anti-HIV therapeutics
with pediatric indications.
Participants in Vice President Gore's Meeting
with Pharmaceutical Companies and AIDS Researchers
2/20/96
The following pharmaceutical company representatives participated
in the February 20 meeting on AIDS drug development with Vice
President Gore:
Anne-Marie Corrier
President, Chief Executive Officer
BIOSYN
Manuel Navia, PhD
Vice President, Senior Scientist
Vertex Pharmaceuticals Inc.
Michael Riordan
President, Chairman
Gilead Sciences
Joseph Pittelli
Senior Vice President for Clinical Research
Wyeth-Ayerst Research
George Morrow
Group Vice President, Commercial Operations
Glaxo Wellcome, Inc.
Dan Hoth
Senior Vice President, Chief Operating Officer
12/20/96 FRI 16:57 FAX 2026321090
AIDS POLICY
003
Cell Genesys, Inc.
Peter Johnson
President, Chief Executive Officer
Agouron Pharmaceuticals, Inc.
Patrick Zenner
President, Chief Executive Officer
Hoffman-La Roche
Rajen Dalal
Vice President for Corporate Planning and Business Development
Chiron Corporation
David Pizzuti
Vice President for Anti-Infective Development and Medical Affairs
Abbott Laboratories
Eve Slater
Senior Vice President for Clinical and Regulatory Development
Merck
##
To Pauline Abernathy
From Tim Westmoreland
Re: Pediatric Drugs
January 7, 1997
I hope that Jennifer Klein has told you that I will be contacting you. If
not, this note will seem a little odd.
For almost two years now, I have been working with the Pediatric AIDS
Foundation (PAF, the group founded by the late Elizabeth Glaser, now headed
by Susan DeLaurentis) to try to improve the pediatric research on
pharmaceuticals. In this case, we are talking about all drugs, not just AIDS
drugs (since FDA estimates that 80% of all drugs now on the market have no
pediatric data), although AIDS drugs are a particular problem that is
particularly visible.
In addition to a nearly (but not quite) successful legislative initiative
with Senator Kassebaum and Congressman Greenwood last session, we have been
working with FDA to see if there is some regulatory action that might be
taken to correct the problem. While initially skeptical that there was much
they could do except use the bullypulpit with the industry, they now have
become very supportive. I think that you will find that David Kessler, Bill
Schultz (his deputy), and their lawyers are interested.
It is also my understanding that friends of the PAF have met with Mrs.
Clinton personally about this topic and that she expressed interest.
In very brief (if you'd like, I'll send you the background memo on this), we
have argued that the Food, Drug and Cosmetic Act does not allow the
Commissioner to approve a drug without pediatric data. The Act says "safe
and effective, not "safe and effective for adults only." Supporting this
argument, the legislative history is replete with references to kids. There
are other arguments (about labeling and misbranding drugs that kids will
use).
I am writing now because I understand that there is to be a meeting tomorrow
(Wednesday) with Greg Simon, et. al., and a group called the AIDS Policy
Center for Children, Youth, and Families, represented by David Harvey. I am
concerned that the work we have done with the FDA and the White House not be
discussed at this meeting. I would caution you that, good cause that he
represents, David sometimes discusses issues with others after meetings that
should best be kept for another day. I would hate for the pharmaceutical
industry types to hear about this before the FDA or the White House is
prepared to act.
Toby Donnenfield (sp?) has invited the Pediatric AIDS Foundation to attend
this meeting also, although I am in London until the end of the month.
Others could certainly attend in my place, but I am inclined to agree with
Toby's suggestion that this meeting proceed and that we plan a second one.
I am writing now to ask your help. If you attend this meeting tomorrow, will
you try to ensure that the PAF proposals are not discussed as such and that
nothing gets to the industry people? I have sent a message to Chris Jennings
as well, although he will not be attending.
In addition, I hope I can call on your assistance when I return. If you need
anything from me, including background materials, please let me know. You
can also call my office (at Georgetown Law School) and ask for my teaching
assistant, Sharon Perley, who knows this issue and its politics inside and
out (202-662-9595)
.
You can also call me if you'd like
(011-44-171-235-8932) .
Thanks for your time and assistance.
Sincerely,
Tim Westmoreland
12/20
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Insall Love, DeLaurention
Pediatric AIDS Foundation
1311 Colorado Avenue. Santa Monica, California 90404
310-395-9051
Fax 310-395-5149
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Pediatric AIDS Foundation
December 12, 1996
Hope for Children with AIDS
First Lady Hillary Rodham Clinton
BOARD OF DIRECTORS
c/o Pam Cicepti
Paul M. Glaser
The White House
Chairperson
Washington, D.C. 20500
Susan DeLaurentis
Chief Executive Officer
Dear Hillary,
Peter Benzian
Bob Burkett
There's an issue we have been working on for some time and I
Marlene Canter
Philip A. Pizzo. M.D.
want to ask for your help.
Susan Zeegen
Lloyd S. Zeiderman
As we have tried to get HIV drugs to children, we were astonished
Elizabeth Glaser
to learn that 80% of all pharmaceuticals now on the market have
1947-1994
not been tested for safety and effectiveness in children. The Food,
EXECUTIVE ADVISORY BOARD
Drug, and Cosmetic Act requires that drugs be "safe and effective,"
HONORARY CO-CHAIRS
not "safe and effective for adults only."
President and Mrs. Ronald Reagan
Mrs. William E. Brock
We believe the best way to resolve this is to have the President
Alfrea A. Checchi
issue an Executive Order directing the FDA to require that drugs
Kathryn D. Checchi
Kitty Dukakis
that can be used for children be proven safe and effective for them
Michael D. Eisner
Susie Field
before they are approved for adults.
Senator Paula Hawkins
Elton John
We have had contact with Hill leadership and have made some
Michael S. Ovitz
forays into the White House to get reaction to this idea. It would
Steven Spielberg
Jonathan M. Tisch
have been wonderful to make this a holiday gift to all of
Alexander Vreeland
Mrs. Pete Wilson
America's children, but it seems that time is running out. Most
important is that it happen as soon as possible.
HEALTH ADVISORY BOARD
Mary G. Boland. R.N.. M.S.N.
Would you consider interceding on our behalf to make this
happen? There is a sense of urgency to accomplish this before
/vonne Bryson M.D
David Kessler leaves the FDA. We have been discussing this with
Mark Feinberg. MD. Ph.D.
Dr. Kessler and the lawyers at the FDA and feel you will find
Michael S. Corthed. M.D.
them supportive. We have also been in discussions for over a
Margaret C. Heagarty. M.D.
year with Jennifer Klein who has been supportive as well. I am
David D. -0 M.D.
including memos we have prepared with background
Anna Bere naurman M.F.A., M.A.
information and a proposed action plan.
Canier /. Landers M.D.
There has been a great deal of momentum building in support of
Michael McCane M.D.. Ph D
this including a recent Wall Street Journal article. The FDA has
been encouraging drug companies to provide pediatric data but it
.ames Oleske M.D. M.P.H.
just won't save lives until the regulations are changed to
Catherine 5 Peckham. M.D.
require it.
Phillip A. Pizzo. M.D
Thank you for your help.
P3010 Possi. M D.
Are Repinstein. M.D.
Warmest regards,
Invendown 3. Scott. M.D.
Dusan
E Richard Stienm M.D.
Susan DeLaurentis
on Wiener Ph.D A.C.S.W.
Co-founder
Bernard Fields. M.D.
00 FOUNDERS Susan Decaurentis, Elizabeth Glaser Susan Zeegen
1311 Colorado Avenue Senta Monter California 90401
TEL. 13.0 395-905.
FAX
3:01
395
5149
THE WHITE HOUSE
Office of the Press Secretary
For Immediate Release
December 3, 1996
REMARKS BY THE PRESIDENT
AT BEGINNING OF BRIEFING ON AIDS RESEARCH
The Oval Office
11:45 A.M. EST
THE PRESIDENT: This is World Aids Awareness Week - - and
you also know I'm a little hoarse. I'm very excited about the
progress we've made in the last four years. I'm determined to keep
pressing until we have a vaccine and ultimately a cure.
And I'd like to ask the Vice President to sort of take
over for me with the opening remarks, and then we'll hear from
Secretary Shalala. We have some of our nation's top health
officials, our top public health officials here. I thank them for
coming, for their work, and I'd like to ask the Vice President to
speak.
VICE PRESIDENT GORE: Thank you very much, Mr.
President.
As you can tell, the President needs to conserve his
vocal cords a little bit. He's had quite a lot to say about this
topic of AIDS over the last four years, especially internally with
this tremendous team that Secretary Shalala has pulled together and
led on the President's behalf. And this is one of several briefings
that the President has had periodically on the progress our country
is making against HIV/AIDS.
And the experts here will provide some statistics to
back these assertions, but let me just briefly, on behalf of the
President, note that this administration has presided over a 40
percent increase in NIH-supported AIDS research, a 158 percent
increase in Ryan White AIDS Treatment grants, a 24 percent increase
in CDC-HIV prevention activities, a 96 percent increase for HUD's
housing opportunities for people with AIDS program. He has greatly
strengthened the office of AIDS research at NIH and, as a result of
public health service guidelines recommending the use of AZT by
HIV-positive pregnant women and their newborns, there has been a very
encouraging 17 percent drop in the number of infants with perinatally
acquired HIV infections - - those are the last statistics available
from '94 to ' 95 -- also responding rapidly to FDA approval of a new
class of AIDS therapies called protease inhibitors, with increases in
funding for state AIDS drug assistance programs.
We have eased Social Security disability rules to speed
approval of eligibility. And, of course, the President created the
Office of National AIDS Policy at the White House and the
Presidential Advisory Council on HIV/AIDS.
Last year, at the White House Conference on HIV and
AIDS, the President asked me to preside over an effort to look for
ways to overcome obstacles in developing new therapeutics, vaccines,
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and microbacides to combat HIV and AIDS. And we have achieved a
great deal since last year. Working with this team here today, we
convene meetings that led to the establishment of the Forum for
Collaborative HIV Research. And I'm proud that the participants in
this forum - - AIDS clinicians, researchers, drug companies, insurance
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companies, and patient advocacy groups have all expressed their
belief that this has become an unprecedented and productive forum for
discussing the future of HIV research.
These new scientific advancements in HIV and AIDS
treatment optimism and hope in the AIDS community for people with
AIDS and their families. So this is a very positive report this
year. And many our now feeling that there is cause for more optimism
in the near future.
Through collaborative efforts like this new forum, and
the cooperative efforts of the government and private sector
researchers, we'll continue the fight for better and more affordable
prevention strategies, vaccines, and microbacides. We will not
forget the children. The President is personally committed to
focusing this research effort on the crying need to develop pediatric
applications of these prevention and treatment strategies and
products. And we've all talked a great deal about how to do that.
Working with our team assembled here and with our
partners in research, we will continue to knock down every barrier to
the development of successful therapeutics, vaccines, and
microbacides until we knock down the last barrier of all the HIV
virus itself.
Now, on behalf of the President, I want to turn this
over to Secretary Donna Shalala to expand on the administration's
efforts to defeat this terrible disease.
SECRETARY SHALALA: Thank you very much, Mr. Vice
President.
Mr. President, before I start I'd like to present you
with this card. It's actually a thank-you card from the leaders of
public health in the United States. It was presented to me
yesterday, and it says: Dear Mr. President, essentially, thank you,
thank you, thank you for everything that you have been able to do.
And they all signed it. It's in honor of World AIDS Day, which, of
course, was yesterday.
Thank you. Let me begin by first thanking Patsy
Fleming. I know she's announced that she is not going to continue
with us for the second term, and she has done a tremendous job for
you and for the American people.
THE PRESIDENT: She sure has.
SECRETARY SHALALA: She has actually been our coach. I
think all of us would say that Patsy has coached us. She has spent
her career on the AIDS issue, and she spent a lot of time coaching us
to make sure that we had a very focused strategy for this
administration.
The Vice President has outlined some of the successes in
the increase in funds for AIDS. I'd actually like to start with a
chart back there, but I'm not sure I'm going to get to it.
I
Mr, President, can you tell us how you feel about
James Carville's effort to mount an offensive on your behalf?
THE PRESIDENT: I can't comment.
I
You're not going to talk to him about it?
I
How's the Cabinet going?
I
Any decisions, sir?
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