Frequently Asked Questions on
Pediatric Exclusivity (505A),
The Pediatric "Rule," and their
Interaction
The following questions and answers have been
prepared by Pediatric Implementation Team (PdIT) in the Center for
Drug Evaluation and Research (CDER) at the Food and Drug
Administration. This guidance represents the Agency's current
thinking on pediatric exclusivity (505A), the Rule and their
interaction. It does not create or confer any rights for or on
any person and does not operate to bind FDA or the public. An
alternative approach may be used if such approach satisfies the
requirements of the applicable statute, regulations or both.
Q1-Q15:
Exclusivity
Q16-Q32:
The Rule and its Interaction with
Exclusivity
Exclusivity
Section 505(A)
of The Modernization Act enabled FDA to:
- Issue Written Requests for pediatric studies prior to approval
of a new drug application if FDA has determined that information
related to the use of the drugs in the pediatric population may
produce health benefits.
- Issue Written Requests to holders of approved applications for
pediatric studies if it has determined that information related to
the use of the drug in the pediatric population may produce health
benefits.
Section 505(A) also required FDA to develop, prioritize, and
publish a list of approved drugs for which additional pediatric
information may produce health benefits in the pediatric populations
and update it annually.
As an incentive to industry to conduct studies requested by the
Agency, Section 505(A) provides for a 6-month period of marketing
exclusivity (pediatric exclusivity).
Q1. How does a sponsor or applicant qualify for pediatric
exclusivity?
A1. Three essential elements must be in place before an
applicant is eligible for pediatric exclusivity. To qualify
for pediatric exclusivity, the applicant must meet all of the
following conditions:
- Be in receipt of a written request from FDA. On June
30, 1998, FDA issued a
Guidance
for Industry, Qualifying for Pediatric Exclusivity Under Section
505(A) if the Federal Food, Drug, and Cosmetic Act (June 1998).
The guidance describes what constitutes a Written Request and
what it must address. Prior correspondence with applicants
regarding clinical trials, agreements at meetings,
correspondence describing phase 4 commitments, and other
communications with sponsors DO NOT CONSTITUTE a Written
Request. The Written Request describes in detail the
studies needed and the time frame for their completion; the
guidance describes ways in which the Written Request can be
amended to revise the study requirements or the specified time
frame. The Written Request is the key to whether submitted
study reports qualify the applicant for pediatric exclusivity.
- Submit study reports after receipt of the written request.
Firms are to submit reports of studies conducted in pediatric
populations to the FDA after FDA has issued a Written Request.
Under the terms of the statute, FDA must determine whether the
studies submitted meet the terms of the Written Request.
Submissions of reports should generally be in the form of a new
drug application, a supplement to an approved application, or an
amendment to a pending application. A firm should, but is
not required to, obtain approval of pediatric labeling to
qualify for pediatric exclusivity.
- Meet the conditions of the written request. Whether an
applicant qualifies for exclusivity for a product after
conducting the studies and submitting the reports depends on
whether:
- The submission meets the time frame described in the
Written Request, and
- The studies performed meet the terms specified in the
Written Request.
Q2. Can an applicant ask FDA to issue a
Written Request for pediatric studies? A2. Yes. The guidance to
industry describes a process in which a sponsor of a new drug or
the holder of an application for a product on the list may make a
submission to FDA in which it makes a detailed proposal for a
Written Request. Where an applicant has more than one
product containing the active moiety, the proposal should address
each indication that has applicability to pediatric patients and
should propose studies in all appropriate age groups. FDA
encourages applicants to make such proposals. FDA will
review the submitted proposal and MAY issue a Written Request to
the applicant based on the applicant's proposal. Q3. Where should proposals for Written
Requests from applicants be sent? A3. Proposals for Written Requests should
be sent to each of the review divisions with regulatory
responsibility for any of the applicant's products that contains
the same active moiety cited in the Written Request.
Q4. Does a sponsor HAVE to conduct
pediatric studies if it receives a Written Request from FDA? A4. No. A company is not required
to do the studies requested by FDA in a Written Request if it
chooses not to do so. If, however, the applicant decides to
conduct studies that differ from those described in the Written
Request, the applicant will not qualify for pediatric exclusivity
upon submission of the reports thereof. Applicants who
choose to deviate from the studies described in the Written
Request and who are interested in obtaining pediatric exclusivity
should contact the review division and seek to amend the Written
Request prior to the conduct of the studies. The applicant
must receive an amended Written Request prior to submission of the
study reports to NDA. Q5. Can an applicant obtain exclusivity by
submitting an analysis of the literature in response to a Written
Request? A5. Simply compiling the literature on
pediatric use of a drug in a given indication will not qualify an
applicant for pediatric exclusivity. The generous incentives
were made available to stimulate performance of studies necessary
to provide useful information on drug use in children. Q6.
Can the applicant for any approved product qualify for pediatric
exclusivity? A6. No. Pediatric exclusivity is an ADD-ON
to existing marketing exclusivity or patent protection. In
general, products with no patent life or exclusivity remaining
cannot qualify. Under certain conditions, however, pediatric
exclusivity may be granted to a product without remaining
exclusivity IF the supplemental application itself qualifies for a
new exclusivity period under the Drug Price Competition and Patent
Term Restoration Act (Waxman-Hatch Amendments). For example, an
application to extend an approved adult indication to the
pediatric population for a product with no patent life or
exclusivity remaining could obtain pediatric exclusivity IF new
clinical studies of safety and efficacy are required for approval.
In that case, the pediatric supplement would earn 3 years of
marketing exclusivity under the 1984 amendments, to which the
additional 6 month pediatric exclusivity would be added. A
somewhat different situation would be where dosing information was
needed in children under 6 years of age that could be based on PK
studies. An oral solution dosage form exists but has no marketing
exclusivity remaining. However, the firm has a controlled release
product containing the same active moiety that is still protected
by a 3 year exclusivity period. The controlled release product
would not be appropriate for this age group because of the dose
delivered. In this situation, PK studies conducted to label the
oral solution could be the basis of a 6 month extension of the
exclusivity for the controlled release product, provided the terms
of the Written Request are met. Q7.
Does Section 505(A) apply to OTC drugs? A7. Yes. It applies to those
OTC drugs that are the subject of approved NDAs. Q8. Are biologics eligible for pediatric
exclusivity? A8. No. Only drug products subject
to section 505 of the Food, Drug, and Cosmetic Act are eligible
for pediatric exclusivity. CBER, however, regulates a small
number of drug products that are subject to section 505.
These products would be eligible for pediatric exclusivity if the
other statutory conditions are met. Biological products that
are subject to the Public Health Service Act are not eligible for
pediatric exclusivity, even if they have orphan exclusivity or
other patent protection. Q9. For approved drugs, must FDA approve a
supplemental application before pediatric exclusivity is granted?
A9. No. The granting of exclusivity
is not connected to approval; the pivotal factor is whether the
applicant complied with the terms of the Written Request. Q10. How is pediatric exclusivity different
from other exclusivity available under the Waxman-Hatch amendments
or the Orphan Drug Act? A10. Pediatric exclusivity differs from
other exclusivity in the following important ways:
-
Pediatric exclusivity does not accrue only to the product
that was studied in the pediatric population. It attaches
to all the applicant's formulations, dosage forms, and
indications for products with existing marketing exclusivity or
patent life that contain the same active moiety. For
example, if a firm markets an oral formulation, a topical cream,
and an ophthalmic containing the same active moiety and all the
products have remaining marketing exclusivity or patent life,
and if the firm conducts studies regarding the active moiety in
accordance with a Written Request, 6 months additional
exclusivity will be granted to ALL DOSAGE FORMS AND ALL
INDICATIONS with the same active moiety as the drug studied.
- Pediatric exclusivity attaches to the END of all existing
marketing exclusivity and patent periods. Waxman-Hatch
exclusivity, orphan exclusivity, and patent periods run
concurrently.
- Pediatric exclusivity is not tied to approval of labeling
containing information on pediatric use based on the studies
conducted. It may be granted upon acceptance of the study
reports. Acceptance in this context means the Agency has
determined that the studies were conducted in accordance with
the terms of the Written Request and were reported in accordance
with FDA's requirements for filing. Waxman-Hatch and
orphan exclusivity are not granted until approval of the
application.
Q11. What is the list?
A11. The Modernization Act required the
Secretary to "develop, prioritize, and publish a list of approved
drugs for which additional pediatric information may produce
health benefits." As a practical matter, the list consists
of those approved drugs for which there is a pediatric
manifestation of any of the adult indications for which the
product is approved. The list that was made available
by notice in the Federal Register on May 20, 1998 is the priority
section of the list. It is available on the Internet at
http://www.fda.gov/cder/pediatric/peddrugsfinal.htm.
The list will be updated periodically - at least annually.
FDA plans to issue Written Requests for products that appear on
the priority section of the list first. Persons
seeking to add a particular drug to the priority section of the
list or to have a drug removed from the priority section of the
list may submit to the agency a citizen petition that complies
with the requirements of 21 CFR 10.30. Inclusion of a drug
on the list does not necessarily mean that the drug is entitled to
pediatric exclusivity.
Q12. Should a Written Request be issued to
the IND or NDA holder?
A12. If an NDA for the drug product exists,
the Written Request should be issued to the applicant of the NDA.
If no NDA exists for the product, the Written Request should be
issued to the IND holder.
Q13. For over-the-counter (OTC) products
that are the subject of an NDA, which Office Director should sign
Written Requests for pediatric studies?
A13. Consistent with CDER policy for
decision making responsibilities on certain other regulatory
documents that require Office level sign-off pertaining to OTC
drug products subject to NDAs, both the Director of ODE V and the
Director of the Office responsible for the specific subject matter
review division should sign Written Requests for OTC products.
Q14. If a sponsor submits a pediatric study
that meets the terms of a Written Request but the study is not
adequate for inclusion in the labeling, will the sponsor get
pediatric exclusivity?
A14. Yes. Pediatric exclusivity is not dependent on whether
information from the requested study is included in the labeling.
Q15. Where can I get answers to questions
that come up regarding our implementation of the pediatric
exclusivity provisions?
A15. Send questions via E-mail to
pdit@cder.fda.gov. It is an E-mail account that has been set up by the Pediatric
Implementation Team.
The Pediatric "Rule" and Its Interaction with Exclusivity (505A)
The "Rule," effective April 1, 1999, modified 21
CFR Parts 201, 312,314, and 601. It specifies "Regulations
Requiring Manufacturers to Assess the Safety and Effectiveness of
New Drugs and Biological Products in Pediatric Patients."
The "Rule," effective April 1, 1999, modified 21
CFR Parts 201, 312,314, and 601. It specifies "Regulations
Requiring Manufacturers to Assess the Safety and Effectiveness of
New Drugs and Biological Products in Pediatric Patients."
Q16.
What pediatric studies can FDA require a company to conduct
under "the Rule" for each application for a new active ingredient,
new indication, new dosage form, new dosing regimen, or new route
of administration? A16. Under the pediatric rule, FDA can require an applicant to
conduct a pediatric assessment of the product for the indication(s),
dosage form, dosing regimen, or route of administration that is
the subject of the application or supplement. This means that FDA
can require an applicant to assess the safety and effectiveness of
the drug product in the application under review in all relevant
pediatric subpopulations. If FDA deems it necessary, it may
require an applicant to develop a new formulation if it is needed
for use in the targeted pediatric population.
Q17.
What pediatric studies can FDA require a company to conduct for
an approved drug product? A17. Under the rule, FDA has the authority to require pediatric
studies on a drug product for the product's approved indications
IF there is SUBSTANTIAL USE in the pediatric population OR the
product would provide a MEANINGFUL THERAPEUTIC BENEFIT - AND the
absence of adequate labeling could pose significant risk (see 21
CFR 201.23(a)). At this time, however, FDA will not require
studies of approved drugs except if approved by the Center
Director. Instead, FDA will seek to have manufacturers voluntarily
submit studies for marketed drugs under the incentives provided by
FDAMA (see 63 FR 66634 Sec II). For those drugs in which voluntary
measures fail to obtain necessary pediatric studies, FDA will
consider requiring studies.
Q18.
Does FDA ask for the same scope of studies to qualify for
pediatric exclusivity as it does to fulfill the requirements of
the pediatric rule? A18. No. For pediatric exclusivity, FDA will issue a Written Request
for necessary studies on all of the indications that occur in
pediatric populations for which an active moiety is used. A
sponsor does not have to respond to a Written Request. However, a
sponsor must supply all the information asked for in the Written
Request to obtain pediatric exclusivity.
At present, under the pediatric rule, FDA is requiring
applicants to conduct a pediatric assessment only for drug
products and indications contained in applications submitted for
review. The application could be for a new active ingredient, new
indication, new dosage form, new dosing regimen, or new route of
administration. The Agency reserves the right to require studies
on approved indications of a marketed drug as discussed above at
Q17.
Q19.
Under the pediatric rule, does FDA have authority to set a
clock for needed studies to be submitted? A19. Yes. Under 21 CFR 314.55(a), each application for a new active
ingredient, new indication, new dosage form, new dosing regimen,
or new route of administration must contain adequate pediatric
data unless the requirement is DEFERRED (314.55(b)), WAIVED
(314.55(c)), or EXEMPTED (314.55(d) - Orphans). Therefore, under
the rule, for new applications and supplements, the "clock" is the
time of submission of the application. FDA cannot require the
submission of pediatric study reports prior to December 2nd, 2000,
the "compliance date" published in the Federal Register.
Thereafter, necessary pediatric information is required in
applications and supplements for approval. Deferrals of the
requirement for pediatric data will provide a date by which data
submissions are required.
Under 314.55(b) - Deferral - the rule states that FDA may
approve an application for use in adults SUBJECT TO THE
REQUIREMENT that the applicant submits the required assessments
WITHIN A SPECIFIED TIME. However FDA cannot require manufacturers
to submit information before December 2, 2000 (63 FR 66632,
"Compliance dates"). Waiver and exemption remove the requirement
to conduct pediatric studies (and the "clock") with respect to the
particular supplement or application. A waiver may also be
granted only for studies in a particular age group.
Q20. What if a sponsor does not comply with an FDA requirement to
perform a pediatric assessment within the set time?
A20. If an applicant does not conduct a required pediatric
assessment within the set time, the reviewing division should
first notify and meet with the applicant to discuss the reasons
for non submission of the studies within the agreed timeframe. If
the applicant cannot provide a reasonable explanation for the
delay and obtain a deferral from the division, the reviewing
division should pursue appropriate regulatory actions in
Q21.
What if the study submitted is not adequate (not a good study)?
A21. If the study submitted with an application is not adequate, the
sponsor will not have satisfied the pediatric study requirements.
Further study would be necessary unless the requirement is waived.
Presumably, if the adult indications were ready for approval, the
Division could approve the application for adults with a deferral
of the pediatric data until a specified time for completion of the
pediatric requirement.
Please note that an inadequate study that meets the terms of a
Written Request (FDAMA) may still earn pediatric exclusivity, even
if the study is not adequate for approval.
Q22.
Does the firm have to initiate a request for a waiver or can
FDA grant a waiver in the absence of a request from the company?
A22. FDA could waive the requirement without such a request from the
company.
Q23.
Can FDA ask for a new formulation under the pediatric rule? A23. Under the rule FDA not only can ask but can require a new
formulation if it is needed in a pediatric age group that will use
the drug.
Can FDA ask for a new formulation in a Written Request for
pediatric exclusivity?
FDA can request a sponsor to conduct studies in all relevant
pediatric populations. A sponsor will not be able to satisfy such
a Written Request unless it completes studies in all relevant
populations. To complete such studies, a sponsor may need to
develop a new formulation.
Q24.
For the pediatric rule, does the sponsor have to address each
of the pediatric age groups? A24. A sponsor must address all of the pediatric age groups in which
the drug is appropriate for use. FDA considers pediatric patients
to be those aged birth up to the 16th birthday. Age categories are
set as: neonates (0-1 month), infants (1 month to 2 years);
children (2 years to 12 years); adolescents (12 years to 16
years). Sponsors must address the entire age range but need not
necessarily use these specific age categories. If a sponsor bases
its studies on characteristics other than ages, such as
physiological development, the sponsor should support its
categories with scientific, developmental, compliance, or ethical
reasons.
Q25.
When are only pharmacokinetics (PK) needed? A25. Regulations state that where the course of the disease and the
effects of the drug are sufficiently similar in adults and
pediatric patients, FDA may conclude that pediatric effectiveness
can be extrapolated from adequate and well-controlled studies in
adults usually supplemented with other information obtained in
pediatric patients, such as pharmacokinetic studies. Studies may
not be needed in each pediatric age group, if data from one age
group can be extrapolated.
It should be noted, however, that PK/Safety studies in
pediatric population alone would more likely be sufficient if a
drug’s effect is well characterized with regard to the important
PK parameters. Where PK parameters have not been correlated well
with activity in adults (topicals for example), a clinical study
would more likely be required. The study requirements will be
decided on a case by case basis.
Q26. Can FDA require a sponsor to conduct pediatric studies if the
disease only occurs in certain pediatric subpopulations? A26. Yes. FDA can require a sponsor to conduct pediatric studies
even if only a small number of children are affected if the
information would provide a meaningful therapeutic benefit in
pediatric patients. FDA should issue a partial waiver for the age
groups in which the disease does not occur. In addition, if the
sponsor tries to conduct a study in the affected population but
cannot complete the study, perhaps due to a very small number of
patients in which the disease occurs, FDA may issue a waiver.
Q27. Can FDA require a sponsor to conduct preclinical (animal
pharmacology/toxicology) studies in young animals? A27. Yes. The rule requires each application to contain data
adequate to assess the safety and effectiveness of a drug product
in pediatric patients for its claimed use(s) (314.55(a)). If
animal studies are necessary to provide "adequate data" they are
required under the rule. However, each case must be considered on
a case by case basis. There is no standard number or type of
"pediatric preclinical studies" that would be requested. Divisions
should consult with pharmacology/toxicology reviewing staff
regarding the need for any juvenile animal data.
Q28.
FDA receives an application containing a new adult indication
that does not occur in the pediatric population. The agency
knows that the active moiety in the application is also used
off-label for a pediatric indication. Can FDA require the
applicant to conduct pediatric studies on the off-label
indication? A28. No. FDA cannot require an applicant to conduct a pediatric
assessment for off-label indications. However, FDA can issue a
Written Request to the applicant seeking the off-label studies. If
the applicant completed the Written Request, they could qualify
for pediatric exclusivity.
Q29.
If a sponsor submits an application on a drug for which there
are multiple NDAs held by multiple sponsors, who is responsible
for conducting the pediatric assessment? A29. The applicant who submitted the application is responsible for
conducting a pediatric assessment. However, at present FDA would
only require the applicant of the application to conduct the
assessment for the drug product and indication included in the
application.
Q30.
Does each Division make its own decision as to what products,
etc. will be granted waivers? A30. Each Division will make the decisions. The decisions will be
tracked and consistency across divisions will be evaluated.
Q31. Will lack of an acceptable pediatric development plan for a
drug in development be an acceptable reason for FDA to refuse to
file an application? A31. Not at this point. However, sponsors are required to include a
pediatric drug development plan as part of the background package
for the end-of-phase 1 meeting with the division for drugs used
for serious and life threatening diseases or the end-of-phase 2
(EOP2) meeting with the division for other drugs. If this is not
included in the background package, the Division need not grant
the meeting until the background package is complete.
Q32.
Where can I get answers to questions that come up regarding
FDA's implementation of the pediatric "Rule" provisions?
A32.
Send questions via E-mail to
pdit@cder.fda.gov
It is an E-mail account that has been set up by the Pediatric
Implementation Team.
Date created: July 27, 1999 |