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11/25/98 WED 15:56 FAX 301 443 5930
FDA/OFC OF COMM.
001
U.S. FOOD AND DRUG ADMINISTRATION
OFFICE OF THE COMMISSIONER
OFFICE OF POLICY
5600 FISHERS LANE
ROCKVILLE, MARYLAND 20857
OFFICE PHONE: 301-827-3360
FAX PHONE: 301-594-6777
ROOM: 14-105
MAIL CODE: HF-22
TODAY'S DATE: Nov. 25, 1998
THIS FAX IS FOR: Jennifer Klein
FROM: Bill Schultz/Lisa Barclay
FAX NUMBER: (202) 456-2878
NUMBER OF PAGES W/O FAX COVER: 1
COMMENTS: Background materials for the
pediatric labeling final rule.
11/25/98 WED 15:56 FAX 301 443 5930
FDA/OFC OF COMM.
PEDIATRIC LABELING RULE
BACKGROUND. Most drugs and biologics entering the marketplace have not been adequately
tested in children. As a result, product labeling frequently fails to provide directions for safe and
effective use in children. Nevertheless, because children suffer from most of the same diseases as
adults, they are by necessity treated with drugs and biologics lacking adequate directions for their
use. The absence of pediatric labeling information poses a number of dangers to children,
including the risk of under- or over-dosing leading to ineffective treatment or excessive or
unanticipated adverse effects. There are many reported examples of serious adverse reactions in
children exposed to inadequately tested drugs, including seizures and cardiac arrest caused by
bupivicaine, an anesthetic, and withdrawal syndrome in infants and small children following
prolonged administration of fentanyl, a pain killer used as an adjunct to anesthesia. The absence of
adequate pediatric labeling may also result in failure to provide optimal treatment to children
because of the lack of appropriate scientific data. For example, a survey on the use of protease
inhibitors, newest and most promising AIDS drugs, found that, before these drugs were studied in
children, fewer than 10% of children with AIDS were receiving protease inhibitors.
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.
Despite these efforts, the majority of new drugs and biological products still enter the marketplace
insufficiently tested in the pediatric population and the labeling of drugs widely used in children
carries little or no information on pediatric safety and effectiveness. For example, the 1994 rule
requiring manufacturers to survey existing medical literature about the pediatric use of their
products and to add pediatric use information to their labels produced only 65 supplements that
contained adequate labeling information for all relevant pediatric age groups and another 35 with
adequate labeling for some but not all age groups.
The medical and patient communities have strongly urged FDA to take effective steps to increase
the quantity and quality of pediatric labeling.
The agency recognizes that a mixture of incentives and requirements is most likely to lead to
improved pediatric labeling. The FDA Modernization Act of 1997 (FDAMA) included a
provision providing financial incentives in the form of 6 months of market exclusivity to
manufacturers who conduct pediatric studies on some drugs. Although FDA is hopeful that the
FDAMA incentives to produce many additional pediatric studies, the agency believes that this
final rule is still needed to significantly improve the current lack of adequate pediatric labeling.
Because FDAMA exclusivity applies only to products that have exclusivity or patent protection
under the Drug Price Competition and Patent Term Restoration Act and the Orphan Drug Act, it
provides no incentive to conduct studies on certain categories of products, including most
003
11/25/98 WED 15:57 FAX 301 443 5930
FDA/OFC OF COMM.
antibiotics, biologics, and off-patent products. In addition, the voluntary nature of the incentive
provided by FDAMA is likely to leave many drugs, age groups, and indications unstudied. For
example, given limited resources to conduct pediatric studies, it is probable that manufacturers
will elect to conduct pediatric studies on those drugs for which the incentives are most valuable,
i.e., on drugs with the largest adult sales. This may leave unstudied drugs that are greatly needed
to treat pediatric patients, but that have smaller markets. Manufacturers may also elect not to study
drugs that require study in neonates, infants and young children, because studies of these age
groups are particularly difficult and may require the development of new pediatric formulations.
In addition, FDAMA provides exclusivity to a manufacturer who conducts a requested study, even
if the results of the study are inconclusive and do not provide useful information on how to use the
drug in children. Finally, FDAMA does not require manufacturers who conduct pediatric studies
to put the information gained into their drug labels. FDA believes that the final rule will address
many of the gaps left by the FDAMA incentives. Studies conducted under this rule are eligible for
6 months of exclusivity under FDAMA, if they otherwise comply with the statute.
PROVISIONS OF THE REGULATION. The final rule requires applications for new drugs and
biological products to contain sufficient data and information to support directions for pediatric
use for the claimed indications if they (1) provide a meaningful therapeutic benefit to children over
existing treatments, or (2) are likely to be used in a substantial number of pediatric patients. The
required study can be deferred until after approval if, for example, FDA finds that it is appropriate
to delay pediatric studies until sufficient data are collected in adults, or if imposition of the
requirement would delay the availability of a new drug for adults. The requirement can also be
waived if FDA finds, among other things, that the product is likely to be unsafe or ineffective in
pediatric patients, that pediatric studies are impossible or highly impractical, or that reasonable
efforts to develop a pediatric formulation had failed. In response to comments, the scope of the
final rule is broader than the proposed rule. The proposed rule would have applied only to "new
chemical entities" and to never before approved biological products. Many comments argued that
modifications of existing products, may be more clinically significant in the treatment of children
[
that the original products. Therefore, the final rule applies to new active ingredients, new
indications, new dosage forms, new dosing regimens, and new routes of administration.
The rule would also codify FDA's authority to require, in compelling circumstances described in
the regulation, that manufacturers of already marketed drugs and biological products conduct
studies to support pediatric use labeling for the already approved indications. FDA believes that,
in exercising its discretion whether to require studies of already marketed drugs, it is appropriate to
first learn whether manufacturers will undertake the needed studies voluntarily in response to
FDAMA. Therefore, before exercising its authority to require studies of already marketed
products, FDA intends to give the FDAMA incentives an opportunity to produce new pediatric
studies. If manufacturers do not take advantage of the incentives, FDA will then require studies
where there the compelling circumstances described in the regulation are met. FDA expects to
require studies on about 2 drugs per year.
In the event that a manufacturer fails to carry out a required pediatric study, FDA would not seek to
disapprove or withdraw approval of the product, because such an action could deprive adult
patients of important therapies. Instead, FDA would anticipate seeking an injunction from a
federal court requiring the manufacturer to conduct or fund the needed studies.
2
004
11/25/98 WED 15:57 FAX 301 443 5930
FDA/OFC OF COMM.
PEDIATRIC LABELING Qs and As
1.
What does this rule require?
It requires the manufacturers of drugs and biological products that are widely used in children or
that provide a meaningful therapeutic benefit to children to provide information on the safe and
effective use of the products in children, including adequate dosing and safety information. The
information may be required at the time the product is first approved, or may be deferred until a
short time after approval if pediatric studies cannot be completed before the drug is ready for
approval in adults. The rule also authorizes FDA to require manufacturers of marketed drugs and
biologics to study their products in children in compelling circumstances.
2.
Why are you doing this now?
Despite efforts in recent years to address this issue, most drugs still lack adequate pediatric
labeling. Every year more than half of all newly approved drug and biologic products that are
likely to be used in children lack information to support their safe and effective use in children.
Thus, when new drugs enter the market, pediatricians lack information on dosing and safety
necessary to prescribe these products to children who may need them. For products already on
the market, information is eventually made available to physicians by journal articles, handbooks
and other references, but usually years after a drug is approved (and even then the information
isn't available on the label and may not be adequate for some age groups). 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.
Over the years, this lack of information has led to under-treatment and to serious adverse events
in children.
3.
Can't you achieve the same effect through voluntary compliance?
FDA has taken a number of steps in recent years to address inadequate pediatric labeling,
including issuing a rule in 1994 requiring drug manufactures to survey existing data and determine
whether those data are sufficient to give information on how to use a drug in pediatric
populations. These attempts at voluntarily compliance have not worked, as illustrated by the fact
that the majority of drugs important to children still lack adequate pediatric labeling. In response
to the 1994 rule, FDA received approximately 430 supplementary applications for label changes, a
small fraction of the total number of products on the market. Over half of the supplements
submitted simply requested the addition of the statement "Safety and effectiveness in pediatric
patients have not been established." Many others requested minor wording changes or submitted
unorganized, unanalyzed collections of possibly relevant data. Only 15% of the small number of
supplements received (approximately 65) provided adequate pediatric information for all relevant
pediatric age groups, and another 8% (approximately 35) provided adequate pediatric information
for some but not all relevant age groups.
4.
How many comments were received on the proposal and what did they say?
11/25/98 WED 15:58 FAX 301 443 5930
FDA/OFC OF COMM.
FDA received 55 comments on the proposed rule from pediatricians, parents, medical societies,
organizations devoted to specific diseases, and the pharmaceutical industry. The comments from
the pediatric and medical communities and from parents supported the rule, and sought to
broaden its coverage. Many of the comments from the pharmaceutical industry opposed the rule
as unnecessary and beyond FDA's legal authority, although a few supported it.
5.
What changes have been made in the final rule?
In response to comments that the scope of the proposal did not cover those drugs that
would be of most importance to children, the rule now covers new active ingredients, indications,
dosage forms, dosing regimens, and routes of administration. FDA has also responded to many
comments seeking creation of a panel of outside pediatric experts to oversee implementation of
the rule by agreeing to create such a panel and to seek its advice on a range of issues related to
the rule.
6.
Will this requirement hold up drug approvals?
No. FDA will not delay the approval of drugs that are ready to be approved for adults even if
studies in children have not been completed. The rule provides for other methods of ensuring that
the pediatric studies are completed in a timely way.
7.
Given the financial incentives for pediatric studies in the FDA Modernization Act of 1997
(FDAMA) to encourage voluntary compliance, why is this rule necessary?
FDA believes that a combination of incentives and requirements provides the best hope for
improving pediatric labeling. Although FDA is hopeful that the FDAMA incentives will
encourage many new pediatric studies, those incentives are likely to leave a number of important
drugs and age groups unstudied. For example, given limited resources to conduct pediatric
studies, it is probable that manufacturers will elect to conduct pediatric studies on those drugs for
which the incentives are most valuable, i.e., on drugs with the largest adult sales. This may leave
unstudied drugs that are greatly needed to treat pediatric patients, but that have smaller markets.
Manufacturers may also elect not to study drugs that require study in neonates, infants and young
children, because studies of these age groups are particularly difficult and may require the
development of new pediatric formulations. In addition, FDAMA provides exclusivity to a
manufacturer who conducts a requested study, even if the results of the study are inconclusive and
do not provide useful information on how to use the drug in children. Finally, FDAMA does not
require manufacturers who conduct pediatric studies to put the information gained into their drug
labels. FDA believes that the final rule will address many of the gaps left by the FDAMA
incentives. Studies conducted under the rule are entitled to 6 months of exclusivity under
FDAMA if they otherwise satisfy the terms of the statute.
8.
Have children been at risk in the past?
2
006
11/25/98 WED 15:58 FAX 301 443 5930
FDA/OFC OF COMM.
The lack of adequate pediatric labeling has resulted in the use of many products that have only
been tested for adults, causing an increased risk of inappropriate and unexpected adverse effects.
(For example, there were deaths that resulted in neonates from chloramphenicol, an antibiotic.
Other cases in which inadequately studied drugs have resulted in serious adverse effects in
pediatric patients include 1) seizures and cardiac arrest caused by bupivacaine toxicity, a local
anaesthetic; 2) development of colonic strictures in pediatric cystic fibrosis patients after exposure
to high-dose pancreatic enzymes; 3) hazardous interactions between erythromycin, an antibiotic,
and midazolam, a short term anaesthetic; 4) teeth staining from the antibiotic tetracycline; 5)
nuclear jaundice, a skin condition caused by sulfa drugs; and 6) withdrawal symptoms following
prolonged administration of fentanyl, a pain killer used as an adjunct to anesthesia in infants and
small children. These cases occurred from the 1950's through the 1990's.) Also, sometimes
useful drugs not have been used in children because their effects in children were uncertain.
9.
How many drugs that are commonly used in children lack this data?
FDA estimates that over one-half of the drugs approved in the past six years that had potential
usefulness in kids had no pediatric labeling at the time of approval.
10.
What kinds of drugs are commonly missing pediatric data?
Drugs such as anti-asthmatics, steroids, drugs to treat gastrointestinal problems, strong pain
medications, antidepressants, anti-epilepsy drugs, and antihypertensives commonly lack
appropriate pediatric labeling.
11.
What drugs now have the best pediatric data?
Vaccines and antibiotics are the most adequately labeled drugs for children.
12.
How many products will be affected by the rule?
FDA estimates that about 80 drugs and biological products will be studied in children under this
regulation per year. (FDA estimates that a large proportion of these would probably have been
studied voluntarily under the FDAMA incentives, although perhaps not as early.) The rule also
gives the agency authority to review drugs already on the market to determine which ones should
have pediatric studies. FDA intends to see whether manufacturers respond to the FDAMA
incentives for conducting pediatric studies on marketed drugs before imposing any requirements
on this category of products.
13.
Does this regulation cover all drugs?
It covers all drugs and biological products that are used in a substantial number of pediatric
patients or that will provide a meaningful therapeutic benefit to children. If a manufacturer shows
3
11/25/98 WED 15:59 FAX 301 443 5930
FDA/OFC OF COMM.
that a drug will not be used in a substantial number of pediatric patients and will not provide a
meaningful therapeutic benefit to children, the pediatric testing requirement will be waived.
FDA will also waive the requirement if (1) the drug is likely to be unsafe or ineffective in
children; (2) it is impossible or highly impractical to study the drug in children, because, e.g., the
pediatric population is too small or geographically dispersed, or (3) reasonable efforts to develop
a pediatric formulation (if one is needed) have failed.
14.
How will these waivers work and won't they make the regulation meaningless?
The waivers are only intended to be used in those cases in which the drug would not be widely
used and would not represent a meaningful benefit over existing treatment or where the studies
are impossible or highly impractical or pose undue risks to pediatric patients.
15.
What do doctors do when they don't have adequate pediatric safety and effectiveness
information?
Many physicians rely on referenced pediatric handbooks for dosing and use information. (This
information may or may not be based on adequate testing.) Others are reluctant to prescribe
certain products to children without adequate pediatric labeling on the product.
16.
Why haven't companies provided this information in the past?
Some companies do provide this information. However, pediatric labeling has not been required
until now. Lack of familiarity with pediatric studies, need for a pediatric formulation, and cost
may account for the lack of adequate pediatric information.
17.
Would pediatric study participants' lives be at risk if they are entered in studies before all
the data on adults are collected?
Pediatric patients will not be enrolled in studies until enough data on the drug have been obtained
in adults and in animals so that the risk to the pediatric patients does not outweigh the potential
benefits. Children are currently entered into studies of some drugs, for example of antibiotics,
before the drugs are approved in adults. The considerations that will determine when enough data
have been collected in adults to begin pediatric studies under the rule are the same as those
currently used in deciding when to begin studies in children. The timing of pediatric studies will
depend, among other things, on the type of drug being studied, the severity of the disease for
which it will be used, the availability of other adequate treatments, and what is known about the
safety of the drug.
18.
How much will this cost drug manufacturers?
The costs of pediatric studies will be less than 1% of the total costs of developing a drug.
4
008
11/25/98 WED 15:59 FAX 301 443 5930
FDA/OFC OF COMM.
Although some drugs may require more than one study, e.g., for different pediatric age groups,
FDA estimates that an individual pediatric study costs between $100,000 to $150,000. FDA also
estimates that if a company must produce a pediatric formulation, the new formulation an average
of $1,000,000. FDA estimates that the total annual industry costs will be approximately $47
million per year (for an industry with domestic U.S. sales in excess of $66 billion per year). FDA
also estimates that the benefits of the rule will exceed $100,000,000 in reduced health care costs
for children.
FDA has also developed a rough estimate that the FDAMA incentives will be worth
approximately $350-$400 million/year to the pharmaceutical industry.
19.
Will drug prices increase as a result of this regulation?
Because the cost of pediatric studies to manufacturers is expected to be small, it is anticipated that
there will be no significant price increases to patients.
20.
What kind of "legal action" can FDA take to force companies to provide this data on
approved drugs?
FDA can go to court and ask the court to order the company to comply with the regulations. If
the company does not comply, the court can impose penalties.
21.
Why doesn't it cover medical devices? Do we not have this kind of problem with medical
device pediatric data?
Once the agency gains experience in requiring pediatric studies for drugs and biologics, it will
assess the need for such labeling for devices.
22.
What kind of improvement can we expect in our children's health as a result of this
regulation?
We expect safer and more effective medicines for children. The primary benefits expected are the
reductions in avoidable adverse drug reactions and under or over treatments that would result
from better informing health care practitioners about whether, and in what dosages, a given drug
was safe and effective for use in children.
23.
When will this regulation go into effect?
The rule becomes effective 120 days after publication in the Federal Register. Manufacturers of
new drug and biologic products who are required to conduct studies under the rule will have 2
years from the date of publication to comply with the pediatric study requirement. FDA will not
delay the approval of any applications otherwise ready to be approved for adults while awaiting
the submission of pediatric studies required under the rule.
5
11/25/98 WED 16:00 FAX 301 443 5930
FDA/OFC OF COMM.
24.
When can parents expect that information to support safe and effective use of products in
children will become available?
We believe that, in some cases, the information already exists and the drug companies merely
need to analyze and compile it. In these cases, the information can be made available on the
labeling of the products fairly quickly. In other cases, studies need to be conducted. Under the
requirements of our 1994 regulation, where the effects of the product and the disease for which it
is indicated are sufficiently similar in both adults and children, the studies needed can be done
within one year.
6
DRAFT
COPY
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
8
21 CFR Parts 201, 312, 314, and 601
[Docket No. 97N-0165]
RIN 0910-AB20
Regulations Requiring Manufacturers to Assess the Safety and
Effectiveness of New Drugs and Biological Products in Pediatric
Patients
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
SUMMARY: The Food and Drug Administration (FDA) is issuing new
regulations requiring pediatric studies of certain new and
marketed drug and biological products. Most drugs and biologics
have not been adequately tested in the pediatric subpopulation.
As a result, product labeling frequently fails to provide
directions for safe and effective use in pediatric patients.
This rule will partially address the lack of pediatric use
information by requiring that manufacturers of certain products
provide sufficient data and information to support directions for
pediatric use for the claimed indications.
DATES: Effective date. The regulation is effective (insert date
120 days after date of publication in the FEDERAL REGISTER)
Compliance dates. Manufacturers must submit any required
assessments of pediatric safety and effectiveness 20 months after
the effective date of the rule, unless the assessments are waived
or deferred by FDA.
oc98142
2
FOR FURTHER INFORMATION CONTACT:
Khyati N. Roberts,
Center for Drug Evaluation and Research (HFD-103),
Food and Drug Administration,
5600 Fishers Lane,
Rockville, MD 20857,
301-594-6779, or
Karen D. Weiss,
Center for Biologics Evaluation and Research (HFM-570),
Food and Drug Administration,
1401 Rockville Pike,
Rockville, MD 20852,
301-827-5093.
SUPPLEMENTARY INFORMATION:
I. Introduction
In the FEDERAL REGISTER of August 15, 1997 (62 FR 43900)
(hereinafter referred to as the proposal), FDA proposed to
require that manufacturers of certain new and marketed drugs and
biologics conduct studies to provide adequate labeling for the
use of these products in children. As described in the proposal,
children are subject to many of the same diseases as adults, and'
are, by necessity, often treated with the same drugs and
biological products as adults. However, many drugs and
biological products marketed in the United States that are or
could be used in children are inadequately labeled for use in
3
pediatric patients or for use in specific pediatric subgroups
(Refs. 1 and 2). Indeed, many of the drugs and biological
products that are widely used in pediatric patients carry
disclaimers stating that safety and effectiveness in pediatric
patients have not been established (Refs. 2 and 3). Safety and
effectiveness information for some pediatric age groups is
particularly difficult to find. For example, there is almost no
information on use in patients under 2 years of age for most drug
classes (Ref. 1).
As described in more detail in the proposal, the absence of
pediatric labeling information poses significant risks for
children. Inadequate dosing information exposes pediatric
patients to the risk of adverse reactions that could be avoided
with an appropriate pediatric dose. The lack of pediatric safety
information in product labeling exposes pediatric patients to the
risk of age-specific adverse reactions unexpected from adult
experience. The proposal cited reports of injuries and deaths in
children resulting from use of drugs that had not been adequately
tested in the pediatric population. The absence of pediatric
testing and labeling may also expose pediatric patients to
ineffective treatment through underdosing, or may deny pediatric
patients therapeutic advances because physicians choose to
prescribe existing, less effective medications in the face of
insufficient pediatric information about a new medication.
Failure to develop a pediatric formulation of a drug or
4
biological product, where younger pediatric populations cannot
take the adult formulation, may also deny pediatric patients
access to important new therapies, or may require pediatric
patients to take the drug in extemporaneous formulations that may
be poorly or inconsistently bioavailable.
The proposed rule described previous steps taken by FDA in
recent years to address the problem of inadequate pediatric
testing and inadequate pediatric use information in drug and
biological product labeling. FDA's Center for Drug Evaluation
and Research (CDER) and Center for Biologics Evaluation and
Research have implemented a "Pediatric Plan" designed to focus
attention on, and encourage voluntary development of, pediatric
data both during the drug development process and after
marketing. In addition, in the FEDERAL REGISTER of December 13,
1994 (59 FR 64240) (hereinafter referred to as the 1994 rule),
FDA issued a regulation requiring manufacturers of marketed drugs
to survey existing data and determine whether those data were
sufficient to support additional pediatric use information in the
drug's labeling. Under the 1994 rule, if a manufacturer
determines that existing data permit modification of the label's
pediatric use information, the manufacturer must submit a
supplemental new drug application (NDA) to FDA seeking approval
of the labeling change.
Although the preamble to the 1994 rule recognizes FDA's
authority to require drug and biological product manufacturers to
5
conduct pediatric studies on a case-by-case basis, the rule does
not impose a general requirement that manufacturers carry out
studies when existing information is not sufficient to support
pediatric use information. Instead, if there is insufficient
information to support a pediatric indication or pediatric use
statement, the rule requires the manufacturer to include in the
product's labeling the statement: "Safety and effectiveness in
pediatric patients have not been established."
The response to the 1994 rule has not substantially
addressed the lack of adequate pediatric use information for
marketed drugs and biological products. Pediatric labeling
supplements were submitted for approximately 430 drugs and
biologics, a small fraction of the thousands of prescription drug
and biological products on the market. Of the supplements
submitted, approximately 75 percent did not significantly improve
pediatric use information. Over half of the total supplements
submitted simply requested the addition of the statement "Safety
and effectiveness in pediatric patients have not been
established." Others requested minor wording changes or
submitted unorganized, unanalyzed collections of possibly
relevant data. Approximately 15 percent (approximately 65) of
the supplements provided adequate pediatric information for all
relevant pediatric age groups, and another 8 percent
(approximately 35) provided adequate pediatric information for
some but not all relevant age groups.
6
The absence of adequate pediatric use information remains a
problem for new drugs and biologics as well as for marketed
products. The proposal presented data from 1988 through the
1990's showing that the percentage of new products entering the
marketplace with adequate pediatric safety and effectiveness
information has not increased in the last decade.
For example, FDA compared the number of new molecular
entities (NME's) approved in 1991 and 1996 with potential
usefulness in pediatric patients and looked at the adequacy of
pediatric labeling for those drugs. Fifty-six percent (9/17) of
the NME's approved in 1991 with potential usefulness in pediatric
patients had some pediatric labeling at the time of approval. In
1996, only 37 percent (15/40) of the NME's with potential
usefulness in pediatric patients had some pediatric labeling at
the time of approval. For both 1991 and 1996, those drugs
counted as having pediatric labeling may not have been studied in
all age groups in which the drug was potentially useful. The
manufacturers of an additional 7 of the 1991 drugs and 17 of the
1996 drugs promised to conduct pediatric studies after approval.
Since publication of the proposal, figures for 1997 NME's have
become available. In 1997, 39 NME's were approved. Twenty-seven
had potential usefulness in pediatric patients, and 33 percent of
these (9/27) had some pediatric labeling at the time of approval.
Postapproval studies were requested or promised for an additional
six. It is uncertain how many of the commitments made for
7
postapproval studies of the 1996 and 1997 drugs will result in
pediatric labeling. Of the seven NME's approved in 1991 for
which sponsors made commitments to conduct postapproval pediatric
studies, pediatric labeling has been added to only one. This
figure reflects both studies that resulted in positive labeling,
i.e., safety and dosing information, and studies that resulted in
warnings against pediatric use. It does not reflect studies that
failed to provide any useful information about pediatric use or
studies that were completed but the sponsor failed to seek a
change in its pediatric use labeling.
These data indicate that voluntary efforts have, thus far,
not substantially increased the number of products entering the
marketplace with adequate pediatric labeling. FDA has therefore
concluded that additional steps are necessary to ensure the
safety and effectiveness of drug and biological products for
pediatric patients. This rule requires the manufacturers of new
and marketed drugs and biological products to evaluate the safety
and effectiveness of the products in pediatric patients, if the
product is likely to be used in a substantial number of pediatric
patients or would provide a meaningful therapeutic benefit to
pediatric patients over existing treatments.
In addition to issuing this rule, FDA has initiated other
actions that it hopes will encourage the development of adequate
pediatric use information. FDA plans to develop additional
guidance on how to develop effectiveness, safety, and dosing
8
information to support pediatric labeling. The agency also
supported a provision in the reauthorized Prescription Drug User
Fee Act (PDUFA) eliminating user fees for pediatric supplements
to encourage the submission of these supplements.
Finally, FDA has issued a guidance document entitled
"Providing Clinical Evidence of Effectiveness for Human Drug and
Biological Products, " describing the kinds of studies that can
support effectiveness in supplemental or original applications.
In that document, FDA provides guidance to manufacturers on the
circumstances in which FDA may approve an initial or supplemental
claim in which substantiation of the results of an adequate and
well-controlled trial is provided by information other than a
second adequate and well-controlled trial precisely replicating
the first trial, or the circumstances in which studies without
the extensive documentation ordinarily required could be
utilized. This guidance will often be relevant to the data
needed to support claims in a pediatric population.
Since the issuance of the proposal, Congress has enacted a
bill that has an impact on pediatric studies of certain drugs.
The Food and Drug Administration Modernization Act of 1997
(FDAMA) (Pub. L. 105-115) contains provisions that establish
economic incentives for conducting pediatric studies on drugs for
which exclusivity or patent protection is available under the
Drug Price Competition and Patent Term Restoration Act (Pub. L.
98-417) and the Orphan Drug Act (Pub. L. 97-414). These
9
provisions extend by 6 months any existing exclusivity or patent
protection on a drug for which FDA has requested pediatric
studies and the manufacturer has conducted such studies in
accordance with the requirements of FDAMA. FDAMA also
specifically recognizes FDA's intention to require pediatric
studies by regulation and extends by 6 months any existing
exclusivity or patent protection on a drug whose manufacturer
submits pediatric studies in compliance with this rule, if the
studies meet the completeness, timeliness, and other requirements
of section 505A. Under FDAMA, a manufacturer who submits
pediatric studies required under this rule may receive a 6-month
extension of exclusivity or patent protection granted to the
manufacturer for that drug.
Although FDA expects the exclusivity offered by FDAMA to
provide a substantial incentive for sponsors to conduct some
pediatric studies, the agency nonetheless believes that this
final rule is necessary to significantly increase the number of
drug and biological products that have adequate labeling.
Certain limitations on the scope and effect of the exclusivity
offered by FDAMA are likely to leave significant gaps in
pediatric labeling. For example, because FDAMA exclusivity
applies only to products that have exclusivity or patent
protection under the Drug Price Competition and Patent Term
Restoration Act and the Orphan Drug Act, it provides no incentive
10
to conduct studies on certain categories of products, including
most antibiotics, biologics, and off-patent products.
In addition, the voluntary nature of the incentive provided
by FDAMA is likely to leave many drugs, age groups, and
indications unstudied. Given limited resources to conduct
pediatric studies, it is probable that manufacturers will elect
to conduct pediatric studies preferentially on those drugs for
which the incentives are most valuable, i.e., on drugs with the
largest sales. This may leave unstudied drugs that are greatly
needed to treat pediatric patients, but that have smaller
markets. For similar reasons, manufacturers are less likely to
seek FDAMA exclusivity by conducting studies on drugs that
require studies in neonates, infants, or young children. The
youngest pediatric populations are more difficult to study and
may require pediatric formulations, making pediatric studies of
these groups more expensive, thereby reducing the value of the
incentives provided by FDAMA. Thus, where there is a great
medical need for data on drugs with relatively small markets or
for studies on neonates, infants, or young children, it may be
necessary to require the collection of such data, rather than
rely on incentives.
Finally, manufacturers are eligible for FDAMA exclusivity
when they submit a study to FDA that is consistent with FDA's
written request for such a study. The study results are not
required to provide useful information on pediatric use (e.g.,
11
the results may be inconclusive), and the sponsor is not required
to obtain approval of a supplement adding the information gained
in the study to the drug's label. Thus, FDAMA provides no
guarantee that the studies conducted under the statute will
result in improved pediatric labeling.
For these reasons, FDA believes that there remains an
important need for this rule. FDA has concluded, however, that
with respect to already marketed drugs eligible for exclusivity
under FDAMA, the publication of the list required by section
505A (b) and the availability of pediatric exclusivity may diminish
the need to exercise the agency's authority to require studies.
Under the rule, FDA has discretion whether to require studies of
marketed drugs (see § 201.23 (21 CFR 201.23) ) FDA believes
that, in exercising its discretion under § 201.23, it is
appropriate to determine whether manufacturers will undertake the
needed studies voluntarily. FDA will therefore allow an adequate
opportunity for manufacturers voluntarily to submit studies for
drugs listed by FDA as having a high priority. If, following
such an opportunity, there remain marketed drugs for which
studies are needed and the compelling circumstances described in
the rule are met, the agency will consider exercising its
authority to require studies. With respect to marketed drugs and
biologics that are not eligible for exclusivity under FDAMA, FDA
intends to exercise its authority to require studies as of the
effective date of the rule in the circumstances described in the
12
regulation. FDA emphasizes that the appearance of a drug or
biologic on the list published under section 505A (b) carries no
implication that FDA will require studies on that drug or
biologic under this rule. FDA intends to reserve its authority
to require studies of marketed drugs and biologics to situations
in which the compelling circumstances described in the regulation
are present.
FDA intends to issue further regulations and guidance
implementing the pediatric exclusivity provisions of FDAMA, which
will, among other things, provide guidance on the interaction of
this rule and FDAMA exclusivity.
II. Highlights of the Final Rule
This final rule is designed to ensure that new drugs and
biological products contain adequate pediatric labeling for the
approved indications at the time of, or soon after, approval.
The final rule establishes a presumption that all new drugs and
biologics will be studied in pediatric patients, but allows
manufacturers to obtain a waiver of the requirement if the
product does not represent a meaningful therapeutic benefit over
existing treatments for pediatric patients and is not likely to
be used in a substantial number of pediatric patients. The rule
also authorizes FDA to require pediatric studies of those
marketed drugs and biological products that: (1) Are used in a
substantial number of pediatric patients for the claimed
indications, and where the absence of adequate labeling could
13
pose significant risks; or (2) would provide a meaningful
therapeutic benefit over existing treatments for pediatric
patients, but whose labels do not provide adequate information to
support safe and effective use in pediatric patients for the
approved indications.
A. Scope of Rule
The proposed rule would have required an application for a
drug classified as a "new chemical entity" or a new (never-
before-approved) biological product to contain safety and
effectiveness information on relevant pediatric age groups for
the claimed indications. Based upon comments observing that
changes in already marketed chemical entities, such as new
indications or dosage forms, can have as much or more therapeutic
significance for pediatric patients than the original product,
the final rule expands the scope of the rule to include new
active ingredients, new indications, new dosage forms, new dosing
regimens, and new routes of administration for which an applicant
seeks approval. The final rule does not, however, require the
submission of pediatric data for a drug for an indication or
indications for which orphan designation has been granted under
section 526 of the Federal Food, Drug, and Cosmetic Act (the act)
(21 U.S.C. 360bb)
B. Types of Studies Needed
As described in the 1994 final rule, gathering adequate data
to establish pediatric safety and effectiveness may not require
14
controlled clinical trials in pediatric patients. Where the
course of the disease and the product's effects are similar in
adults and pediatric patients, FDA may conclude that pediatric
safety and effectiveness can be supported by effectiveness data
in adults together with additional data, such as dosing,
pharmacokinetic, and safety data in pediatric patients. The rule
also does not necessarily require separate studies in pediatric
patients. In appropriate cases, adequate data may be gathered by
including pediatric patients as well as adults in the original
studies conducted on the product.
The specific pediatric information needed in each case will
depend on the nature of the application, what is already known
about the product in pediatric populations, and the underlying
disease or condition being treated. The final rule requires an
assessment of safety and effectiveness in pediatric patients only
for the indications claimed by the manufacturer. It does not
require a manufacturer to study its product for unapproved or
unclaimed indications, even if the product is widely used in
pediatric patients for those indications. In the proposed rule,
the pediatric study requirement for drugs was contained in
§ 314.50 (g) (21 CFR 314.50(g)). In the final rule, the
requirement is located in new § 314.55, because § 314.50 does not
contain other specific study requirements. The location of the
requirement for biological products (§ 601.27 (21 CFR 601.27) )
remains unchanged in the final rule.
15
C. Age Groups
The final rule requires pediatric studies in each age group
in which the drug or biological product will provide a meaningful
therapeutic benefit or will be used in a substantial number of
pediatric patients for the indications claimed by the
manufacturer. The relevant age groups will, however, be defined
flexibly, depending on the pharmacology of the drug or biological
product, rather than following the fixed age categories defined
in the 1994 rule and identified in the preamble to the proposed
rule. For drugs and biological products that offer a meaningful
therapeutic benefit, the rule requires manufacturers to develop
pediatric formulations, if needed, for those age groups in which
studies are required. Manufacturers may, however, avoid this
requirement if they demonstrate that reasonable attempts to
develop a pediatric formulation have failed.
D. Not-Yet-Approved Products
1. Deferral of Studies Until After Approval
The final rule permits the submission of pediatric
information to be deferred until after approval if there is an
adequate justification for deferral, e.g., because pediatric
studies should not begin until some safety and/or effectiveness
information on adults has been collected, or awaiting the
completion of pediatric studies would delay the availability of a
product to adults. When trials should begin in particular cases,
and whether deferral will be necessary, will depend upon the
16
seriousness of the disease for which the drug or biological
product is indicated, the need for the product, the amount of
safety and effectiveness data available, and what types of
pediatric studies are needed.
In general, FDA expects that studies of drugs or biological
products for diseases that are life threatening in pediatric
patients and that lack adequate therapy could begin earlier than
studies of drugs that are less urgently needed, ordinarily as
early as the availability of preliminary safety data in adults
(frequently referred to as phase 1 data), even if data from well-
controlled studies are not yet available. For less critical
drugs and biologics, pediatric studies could ordinarily begin
when additional safety and/or effectiveness data from the initial
well-controlled trials in adults (frequently referred to as phase
2 data) became available. Of course, studies of products for
exclusively pediatric diseases ordinarily need not await the
development of adult data. The timing of individual pediatric
studies will, however, necessarily depend on the specific
information available about the product in question. For
example, a study of a noncritical drug in adolescents might begin
after the initial safety studies in adults, if all the parties
involved agreed that initiation was appropriate in light of the
results of the adult and animal safety studies.
In other cases, studies should not begin in pediatric
patients until significantly more adult data are collected. For
17
example, FDA does not believe that early study or use in
pediatric patients is appropriate for some so-called "me-too"
drugs that are expected to be widely used but are members of a
drug class that already contains an adequate number of approved
products with pediatric labeling. Such drugs may not have been
shown to provide any benefit over other products in the same
class, and may introduce new risks that are not apparent until
the drug has been in wide use after marketing. Studies of such
drugs will therefore usually be deferred until the safety
profiles of the drugs are well established through marketing
experience. To encourage use of properly labeled drugs in
pediatric patients, FDA may require the pediatric use section of
the approved labeling of such a me-too drug to contain a
statement recommending preferential use of other drugs that are
adequately labeled for pediatric use.
2. Waiver of the Study Requirement
The pediatric study requirement applies to all applications
for new active ingredients, new indications, new dosage forms,
new dosing regimens, and new routes of administration, unless FDA
waives the requirement. Under criteria established in the rule,
FDA may waive the study requirement for some or all pediatric age
groups. The burden is on the sponsor to justify a waiver. A
waiver will be granted if the waiver request demonstrates that
the product meets both of the following conditions: (1) The
product does not represent a meaningful therapeutic benefit for
18
pediatric patients over existing treatments, and (2) the product
is not likely to be used in a substantial number of pediatric
patients. There was some confusion in the comments on the
proposed rule over these waiver criteria. FDA emphasizes that
the study requirement applies to a product that offers a
meaningful therapeutic benefit even if it is not used in a
substantial number of pediatric patients, and vice versa.
In response to comments, FDA has refined its definitions of
"meaningful therapeutic benefit" and "substantial number of
pediatric patients. To define meaningful therapeutic benefit
for both drugs and biologics covered by this rule, FDA has
relied, in part, on CDER's current administrative definition of a
"Priority" drug, applied to pediatric populations. The
administrative definition of "Priority" products for biologics
relies on different criteria (Ref. 2). Use of CDER's Priority
drug definition to help define "meaningful therapeutic benefit"
is not intended to affect the administrative definition of a
Priority biologic. The Priority classification for drugs is
determined based on CDER's estimate, at the time of NDA
submission, of a drug's therapeutic, preventive, or diagnostic
value. A Priority drug is defined as one that, if approved,
would be a significant improvement in the treatment, diagnosis,
or prevention of a disease, compared to marketed products
approved for that use. In establishing meaningful therapeutic
benefit for pediatric use, the comparison will be to other
19
products adequately labeled for use in the relevant pediatric
population. If there are no such products, a new product would
usually be considered to have a meaningful therapeutic benefit.
Improvement over existing products labeled for pediatric use can
be demonstrated by, for example: (1) Evidence of increased
effectiveness in treatment, prevention, or diagnosis of disease;
(2) elimination or substantial reduction of a treatment-limiting
drug reaction; (3) documented enhancement of patient compliance;
or (4) evidence of safety and effectiveness in a new
subpopulation. Evidence of improvement over existing therapies
need not in all cases come from head-to-head trials.
To help ensure that pediatric patients have a sufficient
range of treatments available, a product will also be considered
to provide a meaningful therapeutic benefit if it is in a class
of products or for an indication for which there is a need for
additional therapeutic options, notwithstanding the fact that it
might not be a priority drug. In contrast to the range of
therapies for a given indication often available to adults, there
are relatively few instances in which therapeutic alternatives
are studied and labeled for pediatric patients. For some
diseases, however, it is therapeutically important to have a
range of available treatment options, e.g., because there are
frequent treatment failures. The Priority definition would cover
the first product labeled for pediatric use, but might not cover
the second or third product for a given indication or in a given
20
class, if the subsequent product did not offer an advantage over
existing therapies. The specific number of products needed will
depend upon such factors as the severity of the disease being
treated and the adverse reaction profile of existing therapies.
FDA will seek further guidance on applying this criterion from a
panel of pediatric experts.
Thus, new products will meet the definition of a meaningful
therapeutic benefit if: (1) They provide a significant
improvement over existing adequately labeled therapies; or (2)
if they are indicated for diseases or conditions, or are in
product classes, in which there are currently few products
labeled for pediatric use and more therapeutic options are
needed. FDA expects that over time, as the number of products
adequately labeled for pediatric patients grows, the number of
new products meeting the second criterion will diminish. FDA
emphasizes that the addition of the second criterion for defining
meaningful therapeutic benefit under this final rule is not
intended to alter the definition of a Priority drug, and that
products meeting the second criterion will not thereby be
eligible for Priority status. FDA also notes that the rule's
definition of meaningful therapeutic benefit is intended to apply
only in the pediatric study context.
FDA has also revised the proposed definition of "a
substantial number of pediatric patients. Several comments
argued that FDA should rely on the definition of a rare disease
21
in the Orphan Drug Act as a disease affecting fewer than 200,000
patients, because Congress could be said to have considered more
than 200,000 a substantial number for purposes of developing a
new indication. Developing adequate directions for use of a drug
or biologic in pediatric populations usually represents a
substantially smaller task than establishing the effectiveness
and safety of a product in the first instance. Although in some
cases, controlled trials may be needed, this will not often be
the case and, where needed, a single controlled trial would
usually suffice. More commonly, what will be needed would be
safety experience and pharmacokinetic or pharmacodynamic studies.
Reflecting this considerably smaller effort, FDA will use the
percentage of the population under 16 years of age, calculated
using recent U.S. Census data, (approximately 23 percent in 1998)
(Ref. 3) and multiply it by 200,000 to determine the number of
pediatric patients with the disease or condition that will be
considered a substantial number. Thus, more than 46,000
pediatric patients affected by a disease or condition would
currently be considered a substantial number. This definition of
"a substantial number of pediatric patients" (percentage of
population under 16 years of age multiplied by 200,000) has not
been codified, however, and FDA may modify it, after consulting
with a panel of pediatric experts. Any modification will be
issued in a guidance document with an opportunity for comment.
22
FDA will also waive the pediatric study requirement where:
(1) The applicant shows that the required studies on the product
are impossible or highly impractical because, for example, the
population is too small or geographically dispersed; (2) the
product is likely to be unsafe or ineffective in pediatric
patients; or (3) reasonable efforts to develop a pediatric
formulation (if one is needed) have failed.
To reduce the burden on manufacturers in applying for
waivers and deferrals, FDA intends to issue a guidance document
providing a format for a request for waiver or deferral.
E. Marketed Products
The final rule is also intended to improve pediatric use
information for already marketed drugs and biological products.
The rule codifies FDA's authority, discussed in the 1994 rule, to
require, in the compelling circumstances described in the
regulation, that manufacturers of already marketed drugs and
biological products conduct studies to support pediatric-use
labeling for the claimed indications. The criteria for requiring
studies of marketed products have been revised slightly in
response to comments.
F. Early Discussions and Pre- and Postmarket Reports
The final rule contains provisions designed to encourage
discussions of the need for pediatric studies early in the drug
development process, as well as pre- and postmarketing reporting
requirements designed to assist FDA in determining whether
23
pediatric studies are needed for particular products and whether
required studies are being carried out with due diligence.
G. Pediatric Committee
Many comments on the proposed rule urged FDA to form a
committee of outside experts to assist in various aspects of the
implementation of the rule. FDA has concluded that such a panel
could provide useful advice and experience. FDA will convene a
panel of pediatric experts, including at least one industry
representative, and seek its advice on a range of issues related
to implementation of the rule, including: (1) The agency's
implementation of all aspects of the final rule, including its
waiver and deferral decisions; (2) which marketed drugs and
biological products meet the criteria for requiring studies; (3)
when additional therapeutic options are needed for a given
disease or condition occurring in pediatric patients; (4)
ethical issues raised by clinical trials in pediatric patients;
(5) the design of trials and analysis of data for specific
products or classes of products; and (6) issues related to the
progress of individual studies.
H. Remedies for Violation of the Rule
For violations of this rule, FDA would ordinarily expect to
file an enforcement action for an injunction, asking a Federal
court to find that the product is misbranded under section 502 of
the act (21 U.S.C. 352) or is an unapproved new drug under
section 505 (a) of the act (21 U.S.C. 355) or an unlicensed
24
biologic under section 351 of the Public Health Service Act, and
to require the company to submit an assessment of pediatric
safety and effectiveness for the product. Violation of the
injunction would result in a contempt proceeding or such other
penalties as the court ordered, e.g., fines. FDA does not
intend, except possibly in rare circumstances, to disapprove or
withdraw approval of a drug or biological product whose
manufacturer violates requirements imposed under this rule.
III. Comments on the Proposed Rule
FDA received 54 written comments on the proposed rule from
pediatricians, professional societies, parents, members of the
pharmaceutical industry, organizations devoted to specific
diseases, and patient groups. A significant majority of the
comments, primarily those from pediatricians, professional
societies, parents, organizations devoted to specific diseases,
and patient groups, supported regulations requiring that drugs
and biologics be studied in children. Many of these comments
described the problems faced by the pediatric community and
parents resulting from inadequate pediatric labeling and the
absence of pediatric formulations, and argued that a pediatric
study requirement was long overdue. Some comments, primarily
those from the pharmaceutical industry, opposed a pediatric study
requirement, arguing that existing voluntary measures and
incentives were sufficient to ensure adequate pediatric labeling.
25
Finally, a number of comments addressed FDA's legal authority to
require pediatric testing of drugs and biologics.
FDA also held a day-long public hearing on October 27, 1997,
in Washington, DC, at which recognized experts in the field,
members of the pharmaceutical industry, and other interested
parties were given an opportunity to discuss the issues raised by
the proposed rule. There were three panels, each of which
comprised representatives from industry, the pediatric community,
organizations devoted to specific diseases, patient groups, and a
bioethicist. The panels considered the following three issues:
(1) When pediatric studies are needed, (2) what types of
studies are needed, and (3) special challenges in testing
pediatric patients. Those who spoke were nearly unanimous in
their support for some kind of regulation requiring pediatric
studies of some drugs and biologics. There was, however, a wide
range of views on which drugs and biologics should be the subject
of required studies and on how the requirement should be
implemented.
Many written and oral comments raised specific issues for
consideration by the agency. These comments are addressed below.
A. Purpose of Rule
1. FDA received many comments arguing that this rule is
needed to ensure adequate medical care for children. Many
comments from pediatricians stated that they regularly must
prescribe to young children drugs that are not labeled for
26
children under 6 or even 12, and for which pediatric dosage forms
do not exist. One comment stated that, without adequate testing
and labeling, physicians must estimate appropriate pediatric
doses, and that even at "appropriate" doses, it is not known
whether use in children is as safe as use in adults. One comment
argued that the absence of pediatric labeling puts children at
greater risk for adverse drug reactions (ADR's) and therapeutic
failures than adults. According to another comment, most common
and severe ADR's in pediatric patients would be eliminated by
adequate testing, and that perhaps 2 percent of all pediatric
hospitalizations are due to ADR's. One comment concluded that
the failure to conduct pediatric studies results in a different
standard of care for children and adults in this country.
A comment from a pharmaceutical trade association argued,
however, that most of the toxicity problems identified by FDA as
caused by inadequate pediatric labeling were from the 1950's and
that these "dated" examples are not relevant to current practice.
As an example, the comment cited chloramphenicol, a drug referred
to by FDA in the proposed rule because, when it was used in the
1950's in neonates without adequate testing, it was responsible
for many infant deaths (Ref. 4). According to the comment, it is
now known that chloramphenicol can be used in neonates if the
dose is correct. The comment also stated that practicing
physicians have access to adequate dosing information from case
reports in the medical literature.
27
FDA agrees that the absence of adequate pediatric labeling
puts pediatric patients at risk for adverse drug reactions and
ineffective dosing. FDA believes that the reference to new
dosing information that permits use of chloramphenicol in infants
illustrates the need for this final rule. Had adequate safety
and dosing information been available earlier, many babies' lives
could have been saved. Instead, adequately supported dosing
information was not available until after the drug had been used
in a large number of babies, with tragic consequences. FDA also
disagrees with the comment that the remaining reports cited in
the proposal of unexpected toxicity in pediatric patients from
inadequately tested drugs are "dated." Contrary to the
assertion in the comment, a majority of these reports are from
the 1980's and 1990's (Refs. 5 through 14).
FDA also does not believe that case reports scattered
through the medical literature are an adequate substitute for
organized and complete pediatric labeling information. To the
extent that published experience is informative and credible, it
should be used to improve labeling. The comments received from
pediatricians reflect their view that there is often no
adequately supported dosing and safety information for the drugs
they use routinely in their patients. Even where case reports
are available, they describe a limited number of pediatric
patients and cannot provide sufficient information to establish
the safety profile of a drug in pediatric patients.
28
2. Some comments argued that pediatric studies are needed
because differences between children and adults can make
extrapolation from adult data treacherous. One comment pointed
out that research on antiarrhythmics in pediatric patients has
revealed many surprises in dosing and side effects. For example,
drugs that bind to milk may cause safety or effectiveness
problems in pediatric patients not detected in adults.
FDA agrees that pediatric dosing cannot necessarily be
extrapolated from adult dosing information using an equivalence
based either on weight milligram/kilogram (mg/kg) or body surface
area (mg/m²). There are potentially significant differences in
pharmacokinetics, or unique drug-food interactions, that may
alter a drug's blood levels in pediatric patients. Moreover,
there can be pharmacodynamic differences between adults and
pediatric patients.
3. Several comments argued that voluntary measures have not
resulted in a significant increase in pediatric labeling, and
that new products continue to enter the market without adequate,
or any, pediatric labeling. Pediatricians, professional
societies, parents, organizations devoted to specific diseases,
and patient groups provided many examples of diseases and drug
classes for which pediatric labeling was long-delayed,
inadequate, or nonexistent. Acquired immune deficiency syndrome
(AIDS) drugs were frequently cited as an example of the
industry's failure to obtain adequate pediatric labeling at or
29
near the time of approval. One comment pointed to protease
inhibitors, which are theoretically most effective in newborns
but have not been tested or approved for use in this group. Even
for older children, the comment observed that it has taken over a
year after adult approval to obtain pediatric labeling for these
life-saving drugs. Another comment stated that the absence of
drugs for human immunodeficiency virus (HIV) infection that are
appropriately labeled and formulated for pediatric patients
causes parents to give children inappropriate doses, sometimes
giving up part of their own dose if the child's physician will
not prescribe it.
Other comments pointed out that epilepsy is considered a
pediatric disease but claimed that many new epilepsy drugs are
approved without information for use in pediatric patients.
These comments urged that anti-epileptic drugs be added to the
list of drug classes with inadequate labeling. A comment from a
specialist in pulmonary medicine stated that although asthma is a
common disease in pediatric patients, adult formulations are
often released first, leaving pediatric patients without
effective treatments. Other comments observed that not one of
the standard immunosuppressive medications used in pediatric
patients has been tested in pediatric patients. One comment
contended that poor information about the pharmacokinetics of
these drugs in pediatric patients has led to inadequate dosing to
achieve effectiveness and possibly unnecessary toxicity.
30
The American Psychiatric Association commented that
significant psychiatric diseases are increasingly diagnosed in
pediatric patients, who may be treated with drugs despite the
lack of pediatric labeling. According to this comment, most
psychoactive medications are underutilized in pediatric patients
due to the lack of pediatric labeling and to fear of overdosing.
In the case of anti-hyperactivity drugs, however, the comment
states that as many children are overtreated as undertreated,
especially among pre-school age children. A comment from the
National Institute of Mental Health (NIMH) stated that the rule
was much needed to provide essential data on the safety and
effectiveness of psychiatric medications in pediatric patients.
This comment attached seven NIMH reviews of the existing data on
psychotropic medications for pediatric patients, identifying many
critical knowledge gaps that remain to be addressed by pediatric
research.
One comment stated that pediatric nephrologists frequently
prescribe drugs to pediatric patients for life-threatening
conditions, including antihypertensive medications, diuretics,
lipid-lowering agents, and immunosuppressive agents, even for
pediatric patients less than 2 years of age, without benefit of
formal studies. This comment further stated that drug therapy
for chronic conditions like kidney failure is currently based
only on experience gained from drug usage in children after
approval for the indication in adults, and that discovering
31
"inadequate dosing or severe side effects by empiric use of these
drugs is not desirable or safe." Another comment provided the
results of a survey of 4,898 pediatric patients with end-stage
renal disease on the medications they receive. Ninety-seven
percent received prednisone or prednisolone, 91 percent received
cyclosporine, and 84 percent received azathioprine. According to
the comment, none of these drugs was studied in pediatric
patients and no information on the pharmacokinetics. of these
drugs in pediatric patients is available.
In contrast, several comments from the pharmaceutical
industry argued that voluntary measures, the 1994 rule, and the
incentives provided by FDAMA are adequate to assure adequate
pediatric labeling and that FDA has not given these steps
sufficient time to work. Several comments argued that to obtain
pediatric studies, FDA should use encouragement and early
discussion with sponsors, together with incentives, rather than
imposing new requirements. These comments contended that
sponsors should make "phase 4 commitments" (commitments to
conduct pediatric studies after approval) and FDA should track
these commitments. According to one comment, these methods have
not been systematically used by FDA. According to another
comment, FDA did not describe its present experience in getting
manufacturers to conduct pediatric studies. Other comments
argued that FDA has not allowed the 1994 rule sufficient time to
produce results and that the agency should wait until it has
32
reviewed and acted upon all supplements submitted under that rule
before imposing new requirements. One comment contended that if
the 1994 rule was successful in producing pediatric labeling for
marketed drugs, the new rule should apply only to new drugs. One
comment argued that incentives, including exclusivity, waiver of
user fees, tax credits, and expedited reviews of pediatric
supplements, and liability protection for research physicians,
Institutional Review Boards (IRB's), universities, pharmaceutical
firms, and parents, are the best means of obtaining pediatric
labeling. A few comments argued that excessive litigation will
follow imposition of this rule.
Two comments argued that the 53 NME's approved in 1996
demonstrate that pediatric labeling efforts by the industry are
adequate, and that new requirements are not needed. Although the
figures used in the 2 comments do not agree exactly, these
comments stated that 20 or 21 of the 53 have potential for
pediatric use. According to these comments, of these, 4 have
approved pediatric labeling, 14 have planned or ongoing studies,
1 is switching to over-the-counter (OTC) use, and 1 or 2 have no
immediate plans for pediatric labeling activities. One comment
contended that, between 1990 and 1997, a 28 percent increase
occurred in the number of new drugs in development for pediatric
uses, but provided no data to support this claim.
FDA believes that the current state of pediatric labeling
for drugs and biologics in the United States, as amply
33
illustrated by comments from the pediatric community, is
unsatisfactory. The agency's failure to obtain a significant
increase in labeling for either new or marketed drugs or
biologics through other measures implemented over the last
several years demonstrates the need for a requirement that
sponsors conduct pediatric studies of drugs and biologics that
represent a meaningful therapeutic benefit to pediatric patients
or that will be widely used in pediatric patients. As described
in section I of this document, the response to the 1994 rule has
not produced a significant improvement in pediatric labeling for
marketed drugs. FDA received labeling supplements only for a
small fraction of the drugs and biologics on the market. Of
those supplements it did receive, over half of the submissions
merely sought to add a statement to the product's labeling that
"safety and effectiveness in pediatric patients have not been
demonstrated," and less than a quarter provided adequate
pediatric information for some or all relevant age groups.
The agency's experience in attempting to obtain pediatric
labeling for new drugs entering the marketplace through voluntary
measures has also been disappointing. As described in the
proposal, the percentage of NME's with adequate pediatric
labeling has not increased since 1991, when the agency began
systematic efforts to obtain better pediatric labeling. Although
the number of requests by the agency and commitments by sponsors
to conduct phase 4 (postapproval) pediatric studies may have
34
increased, these requests and commitments have SO far
infrequently resulted in pediatric labeling. Table 1 of this
document displays the results of commitments or requests to
conduct pediatric studies postapproval between 1991 and 1996.
FDA notes that the table does not reflect any labeling
supplements under review.
Table 1. - - Pediatric Labeling
Status of
1991
1992
1993
1994
1995
1996
Totals
pediatric
labeling
NME's approved
30
25
25
22
28
53
183
Pediatric studies
14
11
11
7
14
13
70
not needed
Label includes
9
4
5¹
6¹
5
15
44
some pediatric
use information
or pediatric
studies complete
at time of
approval
Postapproval
7
10
10²
10²,³
10²
17
64
pediatric studies
promised or
requested
Pediatric
1
0
2
4
2
2
11
labeling added
after approval
1
In one case, pediatric use information provided for one of
two approved indications
2 In one case, pediatric data requested for second of two
approved indications
3 In one case, pediatric data requested for additional age
groups
35
As Table 1 of this document reflects, FDA's figures disagree
with those of the comments for the number of 1996 NME's with
potential for pediatric use, the number with some pediatric
labeling at the time of approval and the number for which
commitments or requests for postapproval studies have been made.
The comments did not identify specific drugs, so it is not
possible to determine why the two sets of figures conflict.
Nevertheless, the historical experience reflected in the table
suggests that most of the postapproval pediatric studies for
which commitments were made for the 1996 NME's will not result in
pediatric labeling. Of the 17 commitments to conduct pediatric
studies in 1996, there have thus far been only 2 additions of
pediatric labeling. Although some additional studies supporting
labeling changes may be submitted in the future, the experience
reflected in Table 1 of this document suggests that this will not
be a large number. For example, the 18 promised or requested
studies for the 1991 through 1993 cohorts have resulted in just 3
additions of pediatric labeling 5 to 7 years after approval.
Thus, FDA does not agree that the experience with 1996 NME's
demonstrates the adequacy of current efforts to obtain pediatric
labeling.
None of the comments claiming that the rule will result in
excessive litigation provided any evidence suggesting a
36
relationship between pediatric testing and increased litigation
or liability. As shown in the number of NME's with pediatric
labeling at the time of approval, a significant minority of drug
and biologic manufacturers already conducts pediatric testing.
FDA is aware of no evidence that excessive litigation has been
associated with this testing.
With respect to the argument that the incentives provided by
FDAMA will be sufficient to ensure adequate pediatric labeling,
FDA believes that a mixture of incentives and requirements is
most likely to result in real improvements in pediatric labeling.
FDA is hopeful, e.g., that the FDAMA incentives will make more
resources available for pediatric studies. As described earlier,
FDA does not believe, however, that incentives alone will result
in pediatric studies on some of the drugs and biologics where the
need is greatest. The incentives provided by FDAMA are available
only for drugs already by the exclusivity or patent protection
provided by sections 505 and 526 of the act. Thus, the FDAMA
incentives are not available for many already marketed drugs, or
for many antibiotics or biologics. In addition, limited
resources available to conduct pediatric studies and fiduciary
obligations to shareholders may cause manufacturers to conduct
pediatric studies preferentially on those drugs where the
incentives are most valuable, rather than on those drugs or
biological products where studies are most needed.
37
4. Two comments argued that the rule is inconsistent with a
1977 FDA document entitled "General Considerations for the
Clinical Evaluation of Drugs in Infants and Children, " which
recommended, among other things, that "reasonable evidence of
efficacy generally
*
*
*
be known before infants and children are
exposed to [a drug] "
As described in more detail in section III. D of this
document under "Deferral," FDA expects that for drugs and
biologics other than those for life-threatening diseases without
adequate treatment, clinical trials in pediatric patients will
ordinarily begin no earlier than when initial data from well-
controlled trials in adults (frequently referred to as phase 2
data) become available to ensure that reasonable preliminary
evidence of safety and/or effectiveness is available before
pediatric patients are exposed to the drug or biological product.
How much evidence of safety or effectiveness is "reasonable
evidence" that should be available before pediatric trials may
begin will be determined on a case-by-case basis. Thus, FDA
believes that this rule is substantially consistent with the 1977
document.
FDA notes that the 1977 document was based upon a report
prepared for FDA under a contract with the American Academy of
Pediatrics (AAP) The AAP is currently developing proposed
revisions to this document concerning the types of data needed to
support pediatric labeling. The 1977 document, which falls under
38
the general category of guidance documents, does not bind FDA or
the public, but represents the agency's current thinking on a
particular issue. Alternative approaches may be used if the
alternative satisfies the requirements of the applicable statute
and regulations (62 FR 8961, February 27, 1997) (Good Guidance
Practices document). Until such time as an updated guidance on
the clinical evaluation of drugs in infants and children is
published, sponsors are encouraged to confer with the agency
before initiating pediatric studies.
5. Several comments challenged FDA's use of the 1994 IMS
National Disease and Therapeutic Index (NDTI) data on the 10
drugs used most frequently in pediatric patients without adequate
labeling, arguing that the data incorrectly imply that physicians
have no labeling information, when in fact prescribing
information is now, or will be, available for most of the 10
drugs listed.
These comments misunderstand the purpose for which FDA cited
the 1994 data. Those data provided a snapshot of the labeling
information available to physicians for 10 widely used drugs at a
given point in time. Even if additional information had been
added to the labels of these drugs in the 4 years since the
survey was conducted, there was none available during a year in
which the drugs, together, were prescribed to pediatric patients
over 5 million times. FDA notes, moreover, that, contrary to the
suggestion in the comments, adequate labeling has been added for
39
only 1 of the 10 drugs for the age group described in the
proposal.
6. Two comments disputed the estimated number of times
their products were prescribed to pediatric patients. One
manufacturer argued that the total units sold of Auralgan were
less than the listed number of prescriptions. Another
manufacturer disputed the estimates of Ritalin usage. This
manufacturer also complained that it was not contacted by FDA
about use of Ritalin despite the statement in the proposal that
FDA had contacted the manufacturers of the top 10 drugs used
without adequate labeling in pediatric patients.
Limitations on the data used to estimate number of
prescriptions may have resulted in the discrepancy noted by the
manufacturers of Auralgan or Ritalin. The number of
prescriptions is estimated from data provided by IMS America,
Ltd. IMS NDTI surveys a sample of physicians (more than 2,940
physicians representing 27 specialities) to determine the number
of times that, during patient contacts, physicians mentioned
specific drugs for particular age groups. Physician mentions may
not correlate exactly with actual usage. In addition, the NDTI
numbers taken from the sample of physicians are extrapolated to
the nation as a whole, using a given formula. With respect to
the claim that FDA has not contacted the manufacturer of Ritalin,
FDA notes that it has scheduled meetings with the manufacturer to
40
discuss use of the drug in children, which have been canceled at
the manufacturer's request.
7. One comment challenged FDA's use of quinolones as an
example of a class of drug that does not need to be studied in
pediatric patients. The comment claimed quinolones do need to be
studied in pediatric patients because of their important use in
cystic fibrosis patients.
FDA agrees that fluoroquinolones may provide important
therapeutic benefits to patients with cystic fibrosis. At
present, all approved fluoroquinolones are labeled with the
following statement: "Safety and effectiveness in children and
adolescents less than 18 years of age have not been established. "
In addition, the label includes a statement advising that the
fluoroquinolones cause arthropathy in juvenile animals.
Historically, the agency has recognized a potential therapeutic
role for the fluoroquinolones in children with cystic fibrosis
and hematology/oncology disorders. Indeed, FDA recently approved
ciprofloxacin labeling containing a discussion of cystic fibrosis
experience in the pediatric use subsection. These actions show
that the agency recognizes that there may be a need to study
fluoroquinolones in some pediatric patients.
8. One comment from a pharmaceutical company argued that
serious ethical, legal, medical, and technical difficulties often
prevent conducting pediatric studies. The comment cited
difficulties in enrolling pediatric patients in sufficient
41
numbers, unwillingness of parents to enroll children, and the
absence of pediatric patients with the disease near convenient
and qualified study centers. According to the comment, studies
have been successfully conducted in pediatric patients in the
past where there was a medical need for the drug in pediatric
patients, but this rule will require pediatric studies of drugs
intended for adults that may or may not be administered to
pediatric patients. The comment also contended that the rule
will necessitate a massive infusion of resources for industry,
FDA, and medical speciality organizations, and that the agency
should start with a small list of diseases with similar
pathophysiology in adults and children, and a small list of drug
classes known to have similar metabolism, and plan a graduated
approach.
Contrary to the suggestion in the comment, this rule is
designed to require studies only in those settings in which there
is a significant medical need or where usage among pediatric
patients is likely to be substantial. FDA acknowledges the
difficulties encountered in some cases, but agrees that where
there is a need for studies these difficulties have been overcome
and that pediatric studies have been successfully conducted in
many situations. FDA believes that the number of such studies
already conducted each year, for example of antibiotics,
vaccines, and roughly 25 percent of NME's, support the view that
such studies are not medically, ethically, or technically
42
impossible. FDA also emphasizes that this rule will not require
studies in settings where ethical or medical concerns militate
against studies. As with all studies regulated by FDA, no
pediatric study may go forward without the approval of an IRB,
which is responsible for ensuring that the study is ethical and
adequately protects the safety of the subjects. In addition, the
deferral provisions of the rule are specifically designed to
ensure that no pediatric study begins until there are sufficient
safety and effectiveness data to conclude that the study is
ethically and medically appropriate.
B. Scope
The proposal would have covered only original applications
for those drugs classified as "new chemical entities," including
antibiotics, and new biological products that had never been
approved for any indication. A "new chemical entity,' defined in
21 CFR 314.108 (a), is a drug that contains no previously approved
active moiety. Under the proposal, chemical modifications that
did not change the active moiety, such as the formation of a
different salt or ester of the moiety, would not have required
further study. New indications or dosage forms of a previously
approved moiety also would not have required further studies.
FDA sought comment on whether the requirement should apply more
broadly, e.g., to applications for minor chemical variations of
approved products, new indications, new dosage forms or new
routes of administration.
43
9. A majority of those who commented on the scope of the
rule recommended that the final rule cover all new drugs and
biologics, including new dosage forms and indications, because
modifications in existing drugs may be as therapeutically
significant to pediatric patients as the original drug or
biologic. These comments included pediatricians, medical
societies, one pharmaceutical company, and one disease-specific
organization. Several comments, including two companies, an IRB,
the AAP, a disease-specific organization, and a professional
society recommended including new indications and dosage forms on
a case-by-case basis, generally if their inclusion were
recommended by an expert panel. Several comments supported the
narrow scope of the proposal, including a pharmaceutical trade
association, a professional society, and several companies. The
pharmaceutical trade association suggested that the rule might
also apply to new formulations uniquely suited to pediatric
patients.
FDA has reconsidered the scope of the rule in light of the
comments and has concluded that, in some cases, the need for
pediatric studies is as great for modifications of existing
products and new claims as for the original products. A new
indication or dosage form for a previously approved drug, e.g.,
could be far more relevant to pediatric patients than the
originally approved product. From a public health standpoint,
FDA cannot justify the distinction in the proposal between new
44
chemical entities and never-before approved biologics, on one
hand, and significant modifications of those products, on the
other hand. Therefore, FDA has revised proposed §§ 314.55
(proposed 314.50 (g) ) and 601.27 (a) to cover applications for new
active ingredients, new indications, new dosage forms, new dosing
regimens, and new routes of administration. The final rule
exempts from its coverage any drug for an indication or
indications for which orphan designation has been granted under
the Orphan Drug Act (21 U.S.C. 360bb). FDA believes this
exemption is appropriate because the purpose of the Orphan Drug
Act is to encourage the development of drugs for patient
populations that are SO small as to make the manufacture and sale
of the drug unprofitable if not for the incentives offered by the
Orphan Drug Act. Imposition of a pediatric study requirement on
an orphan drug could conflict with the balance struck by the
Orphan Drug Act, by further raising the cost of marketing the
drug. This exemption does not apply after marketing under
§ 201.23 of this final rule.
FDA's decision to expand the scope of the rule does not
mean, however, that pediatric studies would always be needed for
a new product entering the marketplace, or for a new claim. The
waiver criteria will apply equally to modifications of existing
drugs and biological products. Thus, FDA will require studies
only of those new drugs and biologics that offer a meaningful
therapeutic benefit to pediatric patients or that are expected to
be used in a substantial number of pediatric patients. In many
45
cases, moreover, new dosage forms might need relatively little
pediatric data, such as pharmacokinetic data alone.
10. One comment sought clarification of the applicability
of the rule to generic drugs. The comment argued that the
collection of pediatric data was unwarranted where a generic
manufacturer was copying a drug with an adult dose, and that FDA
should require a pediatric bioequivalence study only where the
innovator submits a supplement for a new dose or regimen in the
pediatric population. Another comment from a generic drug trade
association argued that bioequivalence studies in children should
never be required to support approval of a generic drug.
This rule does not impose any requirements on studies
submitted in support of applications for generic copies of
approved drugs that meet the requirements of section 505 (j) of
the act. FDA also does not currently require bioequivalence
studies to be conducted in children for generic drugs. FDA notes
that petitions submitted under section 505 (j) (2) (C) for a change
in active ingredient, dosage form, or route of administration may
be denied if "investigations must be conducted to show the safety
and effectiveness of" the change. Thus, if a petition is
submitted for a change that would require a pediatric study under
this rule, the petition may be denied.
C. Required Studies
FDA proposed to amend its regulations related to the content
of NDA and biologic license applications (BLA's) to include
46
required information on pediatric studies for certain
applications. Under the proposal, an application for a new
chemical entity or never before approved biologic would have been
required to contain data adequate to assess the safety and
effectiveness of the product for all pediatric age groups for the
claimed indications, unless FDA granted a deferral or full or
partial waiver of the requirement. As described in section III.B
of this document under "Scope", FDA has revised § 314.55 (a)
(proposed § 314.50 (g) (1)) and § 601.27 (a) ) to cover applications
for new active ingredients, new indications, new dosage forms,
new dosing regimens, and new routes of administration. Under the
final rule, all covered applications will be required to contain
data adequate to assess the safety and effectiveness of the
product, unless FDA has granted a waiver or deferral of the
requirement (see "Waiver" and "Deferred Submission" in section
III.D and E of this document).
Assessments required under this section for a product that
represents a meaningful therapeutic benefit over existing
treatments must be carried out using appropriate formulations for
the age group (s) for which the assessment is required, unless
reasonable efforts to produce a pediatric formulation had failed
(see "Waiver" in section III.E of this document) Comments on
issues related to formulation are addressed under "Pediatric
Formulations" in section III.I of this document.
47
The proposal did not mandate particular types of studies.
The proposal recommended that the sponsor consult with FDA on the
types of data that would be considered adequate to assess
pediatric safety and effectiveness in particular cases.
FDA received several comments on the design and conduct of
clinical trials in pediatric patients.
11. One comment asked for clarification of what is meant by
"adequate evidence" to demonstrate safety and effectiveness. The
comment argued that FDA should not require two adequate and well-
controlled trials for pediatric studies, and that the amount of
evidence required should depend on the ability of the data to be
extrapolated from adult to pediatric patients, the seriousness of
the illness to be treated, the ability to assess meaningful
measures of efficacy in pediatric patients, and the feasibility
of conducting adequate trials in relatively uncommon pediatric
disease states. Another comment claimed that the ability to
extrapolate from adult efficacy data is limited and argued that
well-controlled trials in pediatric patients should be the norm.
This comment also stated that safety cannot be extrapolated from
adult data and recommended studying 300 pediatric patients for an
adequate period to identify frequent ADR's. Other comments
questioned the appropriateness of extrapolating from adult
effectiveness data in a variety of settings. One comment argued
that in the area of blood products, in addition to extrapolating
from pharmacokinetic data, it may be appropriate to extrapolate
48
from adult data using relative blood volume replacement. Several
comments urged reliance on a variety of other sources of data,
including published studies and reports, and actual use
information. One comment urged FDA to rely on advanced
scientific and statistical methods that optimize safety,
convenience, and informativeness, while minimizing unnecessary or
uninformative clinical trials.
FDA agrees that "adequate evidence" of safety and
effectiveness for pediatric patients does not necessarily require
two adequate and well-controlled trials. One of two central
purposes of the 1994 rule was to make it clear that pediatric
effectiveness may, in appropriate circumstances, be based on
adequate and well-controlled studies in adults with supporting
data in pediatric patients that permit extrapolation from the
adult data. FDA agrees, however, that extrapolation from adult
effectiveness data would not always be appropriate and that it
may not be appropriate to extrapolate pediatric safety from adult
safety data. FDA has specifically noted, in the FDA guidance
document entitled "Providing Clinical Evidence of Effectiveness
for Human Drug and Biological Products," that if further
controlled trial data were needed in a population subset, it
would usually be sufficient to conduct a single additional
controlled trial. FDA also agrees that useful information can
come from data other than adequate and well-controlled trials,
and encourages the submission of valid and reliable data from a
49
variety of sources. The type and amount of data required in any
particular case will depend upon many factors, including those
cited in the comments.
12. One comment urged FDA, in the final rule, to encourage
sponsors to use Computer-Assisted Trial Design (CATD), allowing
them to reduce number of actual trials in pediatric patients.
FDA encourages the use of any validated scientific method
for designing, conducting, or analyzing clinical trials.
13. One comment questioned whether there will be a
sufficient pool of pediatric subjects to complete trials, in
light of the increase in the number of trials occasioned by the
rule.
FDA believes that with appropriate organization, the pool of
pediatric patients available for studies should be adequate. The
Pediatric Pharmacology Research Units (PPRU's), a network of
groups instituted to conduct pediatric research, some of which
are located outside of major population centers, have an
established record of recruiting pediatric patients and
completing valid studies. Even where the number of pediatric
patients affected by a disease is small, valid studies have
sometimes been successfully conducted. It should also be
reemphasized that many of the studies contemplated under the rule
are pharmacokinetic studies, dose-response studies with short-
term endpoints (pharmacodynamic studies) and safety studies that
are likely to impose relatively little burden on individual
50
patients. Where, however, patient recruitment is so difficult as
to make the study impossible or highly impractical, the rule
permits a waiver of the study requirement (§§ 314.55 (c) and
601.27 (c) )
14. One comment urged that the final rule include a broader
research requirement, and sought to have drug interactions and
drug metabolism taken into consideration. Another comment sought
to have the final rule codify minimal requirements for studies,
such as toxic overdose and pharmacokinetic data. One comment
urged FDA not to codify specific requirements for clinical
trials, but to establish these requirements in consultation with
an expert pediatric committee.
FDA declines to codify specific requirements for pediatric
studies. Flexibility is necessary to assure that required
studies are appropriate for each product. FDA will, however,
consult with a pediatric committee on specific pediatric study
issues.
15. One comment from a professional pharmacy organization
urged that all protocols for pediatric studies be reviewed by
pediatric experts, including a pharmacist knowledgeable about
pharmacodynamic factors in each age group.
FDA reviews protocols for pediatric studies submitted in
investigational new drug applications (IND's), and its reviewers
include experts in pediatrics and pharmacology.
51
D. Deferred Submission
The proposal recognized that there would be circumstances in
which it would be appropriate to permit the submission of
pediatric data after approval. Two such circumstances were
described in the preamble to the proposal: (1) Where adult
safety or effectiveness data need to be collected before the
product could be appropriately studied in pediatric patients, and
(2) where the product was ready for approval in adults before
studies in pediatric patients were completed. Although not
included in the text of the proposal, these examples have been
added to the final rule. Under the proposal, FDA would have the
authority to defer the submission of some or all of the required
pediatric data until after approval of the product for adult use,
on its own initiative or at the request of the applicant. Under
the proposed provisions, if the applicant requested deferral, the
request would be required to contain an adequate justification
for delaying pediatric studies. If FDA concluded that there were
adequate justification for deferring the submission of pediatric
use studies, the agency could approve the product for use in
adults subject to a requirement that the applicant submit the
required pediatric studies within a specified time after
approval. It is important to appreciate that deferred submission
of pediatric data refers to the date on which the data are
submitted, not when the studies are initiated. Thus, deferred
studies will generally be initiated before approval, unless it is
52
concluded that the full adult data base or marketing experience
are needed before pediatric studies may appropriately begin.
FDA stated in the proposal that it would consult with the
sponsor in determining a deadline for the deferred submission,
but tentatively concluded that it would require the submission
not more than 2 years after the date of the initial approval. To
ensure that deferral would not unnecessarily delay the submission
of pediatric use information, FDA proposed that a request for
deferred submission include a description of the planned or
ongoing pediatric studies, and evidence that the studies were
being, or would be, conducted: (1) With due diligence, and (2)
at the earliest possible time. FDA sought comment on the
circumstances in which FDA should permit deferral, and on the
factors that should be considered in determining whether a given
product was one that should be studied in adults before pediatric
patients. FDA received many comments on the deferral provisions
in the proposal.
16. A few comments stated that the deferral provisions are
an appropriate means of assuring that pediatric patients are not
studied before adequate safety data have been gathered. A number
of comments from the pharmaceutical industry asserted, however,
that the proposal would require concurrent testing in adults and
pediatric patients despite medical and ethical reasons for
delaying testing pediatric testing. For example, a comment from
a pharmaceutical trade association claimed that the rule:
53
*
*
*
would require testing of new medical
compounds in children before safety in adults
has been studied adequately, before
effectiveness in adults has been established,
and in young children and neonates without
adequate information about the effects of the
drug in older pediatric patients.
These industry comments appear to have either ignored the
explicit deferral provisions of the rule or perceived them as
rare exceptions to a usual requirement that adults and children
be studied at the same time. Nothing in the rule requires
concurrent testing in adults and pediatric patients, nor testing
in infants and neonates before testing in older children. As
stated previously and in the proposal, the deferral provisions
were specifically included to, among other things, ensure that
pediatric studies could be delayed when necessary to assure that
appropriate safety and/or effectiveness data were available to
support pediatric testing.
17. Most of the comments on deferral focused on whether the
need for safety and/or effectiveness data in adults before
initiating pediatric studies should be a basis for deferral.
Comments from disease-specific organizations, medical societies,
including the AAP, and pediatricians argued that deferrals should
be granted rarely if at all on this basis. One comment argued
that delaying availability of life-saving drugs to children
54
cannot be rationalized scientifically, legally, or ethically, and
contended that deferral should not be permitted for serious and
life-threatening diseases where there is no substantial
difference between the disease or the anticipated effect of the
drug in children or adults. Another comment argued that deferral
should be used sparingly in all age groups, including infants and
neonates, and that its use should be evaluated in the context of
the seriousness of the condition to be treated, the therapeutic
advance the drug represents, and the likelihood that the drug
will be given to children as soon as it is approved. According
to this comment, the risks of research in pediatric patients may
be outweighed by the risks that the drug will be given to them
without data.
One comment argued that pediatric studies of important drugs
should be conducted in parallel to adult studies, especially in
children under 12. Several comments from the pediatric
community, however, supported the development of some adult
safety and/or effectiveness data before initiation of pediatric
studies. One comment from an organization devoted to pediatric
AIDS stated that while the general assumption should be that
pediatric studies will be submitted at the same time as adult
studies, it may be appropriate to have some testing in adults
before children. The AAP stated that it is appropriate to begin
studies in pediatric patients after phase 1 and phase 2 studies
in adults have defined routes of clearance and metabolic
55
pathways. Thus, the comment urged that pediatric studies be
conducted during phases 2 and 3, not 4. A comment from a
nephrology organization argued that drugs for organ-specific
diseases should be studied in phase 3, as soon as phase 1 and 2
trials have shown safety in adults. This and another comment
stated that deferring studies until after approval compromises
clinical trial enrollment, citing the experience with recombinant
erythropoietin. According to these comments, erythropoietin was
not studied in pediatric patients until after its approval for
adults, and enrollment was so difficult that pediatric studies
were not completed for 5 years.
Several comments from the pediatric community also cited
limited circumstances in which they believed deferral to be
appropriate. A medical society argued that data should be
collected after adult studies only for drugs with narrow
therapeutic indices, unusual accumulation in the body, where the
drug study requires extensive blood sampling, or where the study
design places young patients at risk for limited information
gain.
Many comments from the pharmaceutical industry argued, in
contrast, that deferral should be the rule, rather than the
exception. Most of these comments contended that it was
unethical to begin studying drugs in pediatric patients, other
than those that are intended primarily for pediatric patients,
until the drugs are shown to be reasonably safe and effective in
56
adult patients. All argued that pediatric studies must not be
initiated until substantial data in adults are available, but
cited different initiation points, e.g., after phase 2, after
safety and effectiveness is established in adults and an
approvable letter is received, after approval, after 1 year of
marketing.
Although many of these industry comments argued that
pediatric studies should be conducted exclusively as phase 4
(postapproval) commitments, a significant number of industry
comments acknowledged that pediatric studies could begin before
approval, generally after phase 2, and that there were
circumstances in which deferral was not appropriate. One comment
argued that because early pediatric studies often require
pediatric formulations and because up to 50 percent of drugs are
abandoned before phase 3, it is wasteful to require companies to
manufacture a pediatric formulation and begin studies before the
end of phase 2. Another comment argued that no pediatric studies
should begin before the decision to proceed to phase 3, except
where: (1) The disease affects only pediatric patients; (2)
the disease mainly affects pediatric patients, or the natural
history or severity of the disease is different in pediatric
patients and adults; or (3) the disease affects both pediatric
patients and adults and lacks adequate treatment options. One
comment urged that the final rule state that "in most cases,
pediatric testing should not begin with any drug or biological
57
product until certain adult safety and/or effectiveness
information has been collected." According to this comment,
there could be exceptions where no other therapy was available
and there was a potential for the drug to be lifesaving. A
pharmaceutical trade association argued for a presumption that
pediatric studies not begin until the end of phase 2 or 3, but
listed circumstances in which deferral should not occur: (1)
Where the disease is life threatening and there is no alternative
therapy, (2) where the drug is intended for a pediatric
indication, (3) where the drug presents no major safety issues,
(4) where the drug class is well studied in pediatric patients,
or (5) where a large amount of "off-label" use in pediatric
patients is anticipated.
In general, FDA expects that some data on adults will be
available before pediatric studies begin, but that less data will
usually be required to initiate studies of drugs and biologics
for life-threatening diseases without adequate treatment than for
less serious diseases. Pediatric studies of drugs and biologics
for life-threatening diseases may in some cases be appropriately
begun as early as the initial safety data in adults become
available, because the urgency of the need for such products may
justify early trials despite the relative lack of safety and
effectiveness information. In such cases, deferral of submission
of pediatric studies until after approval will be unnecessary,
unless drug development is unusually rapid and the product is
58
ready for approval in adults before completion of the pediatric
studies.
Pediatric studies on products for less serious diseases
should generally not begin until more adult data have been
collected, ordinarily no earlier than the availability of data
from the initial well-controlled studies in adults. As noted
earlier in this document, there may occasionally be exceptions to
this principle where all parties agree that earlier initiation is
appropriate. Whether deferral of submission of the data until
after approval will be necessary for such products will depend
upon when pediatric studies can scientifically and ethically
begin in each case and how difficult the studies are to complete.
In some cases, FDA expects that scientific and ethical
considerations will dictate that studies not begin until after
approval of the drug or biological product. For example,
pediatric studies of "me-too" drugs that do not offer a
meaningful therapeutic benefit and that are members of a drug
class that already contains an adequate number of approved
products with pediatric labeling may be deferred until well after
approval. In cases where a drug has not been shown to have any
benefit over other adequately labeled drugs in the class, the
therapeutic need is likely to be low and the risks of exposing
pediatric patients to the new product may not be justified until
its safety profile is well established in adults through
marketing experience. Because the basis for the deferral in such
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cases will be concern that the drug presents risks to pediatric
patients that will not be known until there is widespread
marketing experience, without offsetting benefit, FDA is revising
the proposal to advise sponsors that FDA may require, in
appropriate cases, that such drugs carry labeling statements
recommending preferential use in pediatric patients of products
that are already adequately labeled. Such a statement might
read:
The safety and effectiveness of this product
have not been established in children. There
are alternative therapies that have been
shown to be safe and effective for use in
children with [indicated condition].
Ordinarily, products already labeled for use
in children should be used in preference to
[name of this product].
Some drugs with no demonstrated advantage over available
therapy can nonetheless be expected to have wide use in pediatric
patients. Pediatric studies of such drugs should be initiated
relatively early, even if they are not completed at the time of
approval.
18. A comment from a pharmaceutical company listed several
circumstances in which it argued FDA should permit deferral: (1)
The pediatric population is SO small that enrollment and
completion of trials cannot be accomplished in parallel with
60
adult trials, (2) the natural course of the disease is different
in adults and children, (3) analytic tools and clinical
methodologies cannot be easily adapted to the pediatric
population, (4) the drug has complex pharmacokinetic properties
in adults making it hard to extrapolate a pediatric dosage range,
(5) the scope and nature of nonclinical studies support only
adult clinical studies, (6) two or more attempts to develop a
pediatric formulation have failed, or (7) unique drug-drug or
drug-food interactions in children confound drug development.
Another comment added to this list: (1) Where fewer than
200,000 pediatric patients are affected by the disease being
treated, and (2) drugs with a low therapeutic index.
FDA agrees that some of these circumstances could make
completion of studies prior to approval in adults difficult, but
does not agree that they would make studies impossible or
impractical in all cases. The need for deferral must be
considered case-by-case. A small pediatric population, e.g.,
might make completion of controlled trials very slow, but might
not prevent obtaining pharmacokinetic data. Simply citing a
pediatric population under 200,000 will not be sufficient to
justify deferral; a small fraction of this number participating
in trials may be sufficient to support timely pediatric studies,
depending on the nature of the studies. As an example, over 70
percent of the estimated 6,000 pediatric patients with cancer
each year are enrolled in clinical trials (Ref. 15) There does
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not seem to be any reason to conclude that deferral is warranted
solely because the natural course of the disease is different in
adults and children. FDA also disagrees that deferral is
necessarily warranted where analytic tools and clinical
methodologies cannot be easily adapted to pediatric patients.
Deferral may be necessary in some cases where the infants and
toddlers are unable to provide subjective outcome data, but it
may also be possible to utilize alternative endpoints or to
extrapolate effectiveness data from older pediatric age groups,
obtaining pharmacokinetic data from the younger age groups to
determine an appropriate dose. Drugs with a low therapeutic
index that do not fulfill an urgent need should, in general, be
studied in pediatric patients later in drug development.
With respect to complex pharmacokinetic properties that
prevent extrapolation of adult data to pediatric patients, low-
therapeutic index drugs, and unique drug-drug or drug-food
interactions in pediatric patients, FDA believes that the need
for pediatric studies before approval is even greater where these
conditions are present; moreover, none of them represents a
significant impediment to studies. Recognizing that drugs and
biologics approved for adults are regularly prescribed to
pediatric patients despite the absence of adequate dosing and
safety data, information positively suggesting that dosing and
safety cannot be extrapolated from adult data increases the
importance of conducting pediatric studies before the product is
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widely used in pediatric patients. The absence of supporting
nonclinical studies (e.g., studies in young animals) should not
usually be a basis for deferral. These studies, if needed, are
readily conducted. Moreover, a full adult data base provides
pertinent safety information that might make further preclinical
data unnecessary. Difficulties in developing an adequate
pediatric formulation may, in some cases, justify deferral of
studies in young pediatric patients. In other cases, however, it
may be appropriate to study a less-than-optimal formulation,
e.g., an injection, if one is available, in pediatric patients
while awaiting the development of a more desirable pediatric
formulation.
19. One comment argued that it was "unacceptable" to defer
pediatric studies to avoid delaying approval for adult use.
Instead, the comment urged FDA to provide a "limited approval"
for adult use until pediatric data are available and impose a
monetary penalty for failure to comply. Another comment argued
that permitting deferral to avoid delay in adult marketing could
be applied to most applications, creating a de facto situation in
which pediatric data were understood to be not required until 2
years after approval. One comment stated that while pediatric
dosing schedules are essential, pediatric studies should not
delay approval of drugs for a major population, adults.
FDA continues to believe that deferral is appropriate where
awaiting the completion of pediatric studies would delay the
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availability of a safe and effective drug or biological product
for adults. Granting a deferral does not automatically mean,
however, that pediatric studies need not be submitted for 2 years
or that initiating them should be long delayed. The proposal
suggested 2 years as the maximum period for a deferral. Where
pediatric studies are supposed to be nearing completion at the
time a product is ready for approval in adults, FDA expects that
the period of deferral would be significantly shorter than 2
years. Where some useful pediatric information, e.g., safety
information, is available at the time of approval, even if some
required studies are not complete, FDA may require that the
pediatric use section of the product's labeling include that
information, to the extent consistent with 21 CFR 201. 57 (f) (9)
FDA also notes that it has no authority to impose a monetary
penalty for failure to submit a required study of a drug or
biological product. FDA must ask a court to impose such a
penalty in a contempt proceeding.
20. Several comments argued that pediatric trials should be
conducted sequentially, beginning with the oldest pediatric age
group, and ending with the youngest. One comment stated that
IRB's would question testing a drug in younger children before
older children. The AAP argued that there is little defense for
studying pediatric patients sequentially from oldest to youngest,
and that such a policy will result in approvals without data in
neonates. This comment argued that the timing of studies should
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give consideration to safety, but without consideration of
sequence. Another comment argued that FDA should not routinely
require that drugs for serious and life-threatening diseases be
studied sequentially. In HIV, according to this comment, drug
testing should be "as simultaneous as possible" because safety
and dosing may be initiated in each age group in a dose
escalating manner regardless of the results in previously tested
groups.
FDA agrees that age-dependent sequential studies are not
necessarily appropriate. Particularly were there is urgent need
for a product, there may be good reason to study older and
younger children at the same time.
21. A few comments objected to FDA's tentative decision to
require the submission of studies ordinarily no later than 2
years after the initial approval. One comment stated that
deferral of up to 2 years was excessive, citing the "critical"
need to ensure timely performance of pediatric studies in
populations where the drug is likely to be used. Another comment
stated that 2 years may be adequate for collecting
pharmacokinetic data, but not necessarily for collecting safety
data. According to this comment, the size of the clinical data
base will be the principal determinant of when data should be
submitted. A comment from the American Red Cross stated that the
extensive IRB review of studies of blood products involving
pediatric patients, and the difficulty in enrolling such
65
patients, makes the 2-year deferral deadline unrealistic for this
category of product.
FDA agrees with the comments that the 2-year deadline
suggested by the proposal may not be appropriate, and that the
length of the deferral should be decided on a case-by-case basis.
The timing of the deferred submission will depend upon such
factors as the need for the drug or biologic in pediatric
patients, when sufficient safety data become available to
initiate pediatric trials, the nature and extent of pediatric
data required to support pediatric labeling, and substantiated
difficulties encountered in enrolling patients and in developing
pediatric formulations. FDA may also extend the date for
submission of studies at the time of approval, e.g., where other
drugs in the class have been approved during the pendency of the
NDA and the new drug is no longer needed as a therapeutic option.
E. Waivers
FDA does not intend to require pediatric assessments unless
the product represents a meaningful therapeutic benefit over
existing treatments or is expected to be used in a substantial
number of pediatric patients. FDA also does not intend to
require pediatric assessments in other situations where the study
or studies necessary to carry out the assessment are impossible
or highly impractical or would pose undue risks to pediatric
patients. Thus, FDA proposed to add § 314.50 (g) (3) (now