Guidance for Industry
How to Comply with the Pediatric Research Equity Act
[PDF version]
Draft Guidance
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20857. All comments
should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions on the content of the draft document contact Grace Carmouze, 301-594-7337 or Leonard Wilson, 301-827-0373.
Additional copies are available from:
Office of Training and Communications
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research (CDER)
Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857
(Tel) 301-827-4573
(Internet) http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Training, and Manufacturers Assistance (HFM-40)
Center for Biologics Evaluation and Research (CBER)
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-144
(Tel) 800-835-4709 or 301-827-1800
(Internet) http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
September 2005
Procedural
TABLE OF CONTENTS
- INTRODUCTION
- BACKGROUND
- OVERVIEW — REQUIREMENTS OF PREA
- PREA STATUTORY REQUIREMENTS
- SCOPE OF REQUIREMENTS
- THE PEDIATRIC ASSESSMENT
- WHAT IS THE PEDIATRIC ASSESSMENT? (SECTION 505B(A)(2) OF THE ACT)
- WHEN TO SUBMIT THE PEDIATRIC ASSESSMENT IN COMPLIANCE WITH PREA
- WHAT TYPES OF DATA ARE SUBMITTED AS PART OF THE PEDIATRIC ASSESSMENT?
- THE PEDIATRIC PLAN AND SUBMISSIONS
- WHEN TO DEVELOP A PEDIATRIC PLAN
- WHAT AGES TO COVER IN A PEDIATRIC PLAN
- MUST A PEDIATRIC FORMULATION BE DEVELOPED?
- WHEN TO INITIATE PEDIATRIC STUDIES
- WHAT INFORMATION SHOULD BE SUBMITTED TO FDA
- WAIVERS AND DEFERRALS
- WHAT IS A WAIVER?
- HOW TO APPLY FOR A WAIVER
- WHAT IS A DEFERRAL?
- HOW TO APPLY FOR A DEFERRAL
- COMPLIANCE WITH PREA
- PREA AND PEDIATRIC EXCLUSIVITY
- ADDITIONAL INFORMATION
- ADDITIONAL INFORMATION CONCERNING PREA
- ADDITIONAL INFORMATION CONCERNING PEDIATRIC EXCLUSIVITY
ATTACHMENT A — SAMPLE WAIVER REQUEST
ATTACHMENT B — SAMPLE DEFERRAL REQUEST
ATTACHMENT C — COMPLIANCE DATES FOR APPLICATIONS SUBJECT TO PREA
Guidance for Industry1
How to Comply with the Pediatric Research Equity Act
Contains Nonbinding Recommendations
Draft - Not for Implementation
This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current
thinking on this topic. It does not create or confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this guidance. |
- INTRODUCTION
This draft guidance provides recommendations on how to interpret the pediatric study
requirements of the Pediatric Research Equity Act (Public Law 108-155) (PREA).
PREA amends the Federal Food, Drug, and Cosmetic Act (the Act) by adding section 505B (21
U.S.C. 355B). PREA requires the conduct of pediatric studies for certain drug and biological
products.2 Specifically, PREA requires new drug applications (NDAs) and biologics licensing applications (BLAs) (or supplements to applications) for a new active ingredient, new indication,
new dosage form, new dosing regimen, or new route of administration to contain a pediatric
assessment unless the applicant has obtained a waiver or deferral (see section 505B(a) of the
Act). It also authorizes FDA to require holders of applications for previously approved marketed
drugs and biological products who are not seeking approval for one of the changes enumerated
above (hereinafter "marketed drugs and biological products") to submit a pediatric assessment
under certain circumstances (see section 505B(b) of the Act).
Although PREA applies to both new applications (or supplements to applications) and already
marketed drugs and biological products, this guidance will only provide recommendations on
NDAs and BLAs (or supplements to an already approved application) for drugs and biological
products under section 505B(a) of the Act. Issues under section 505B(b) of the Act related to
already marketed drug and biological products for which the sponsor is not seeking one of the
enumerated changes may be addressed in future guidance.
This guidance addresses the pediatric assessment,3 the pediatric plan (see section V.A), waivers and deferrals, compliance issues, and pediatric exclusivity provisions.
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
Table of Contents
- BACKGROUND
On December 3, 2003, the Pediatric Research Equity Act (PREA) was signed into law. PREA is
the most recent of more than a decade of legislative and regulatory attempts to address the lack
of pediatric use information in drug product labeling. In PREA, Congress codified many of the
elements of the Pediatric Rule, a final rule issued by FDA on December 2, 1998 (63 FR 66632),
and suspended by court order on October 17, 2002.4
Under the Pediatric Rule, approval actions taken or applications submitted on or after April 1,
1999, for changes in active ingredient, indication, dosage form, dosing regimen, or route of
administration were required to include pediatric assessments for indications for which sponsors
were receiving or seeking approval in adults, unless the requirement was waived or deferred.
The Pediatric Rule was designed to work in conjunction with the pediatric exclusivity provisions
of section 505A of the Act (21 U.S.C. 355a), an incentive signed into law to encourage sponsors
or holders of approved applications to voluntarily perform the pediatric studies described in a
Written Request5 issued by FDA, in order to qualify for an additional 6 months of marketing exclusivity.
On January 4, 2002, the Best Pharmaceuticals for Children Act (BPCA) (Public Law 107-109)
was enacted. The BPCA reauthorized and amended the pediatric exclusivity incentive program
of section 505A and created new mechanisms for funding pediatric studies that sponsors or
holders of approved applications declined to conduct voluntarily. On April 24, 2002, FDA
issued an advance notice of proposed rulemaking (ANPRM) soliciting comments on the most
appropriate ways to update the Pediatric Rule in a manner consistent with other mechanisms for
obtaining studies created by the BPCA.
On October 17, 2002, the U.S. District Court for the District of Columbia held that FDA had
exceeded its statutory authority when issuing the Pediatric Rule and the court suspended its
implementation and enjoined its enforcement (Association of Am. Physicians & Surgeons, Inc.
v. FDA, 226 F. Supp. 2d 204 (D. D.C. 2002)). When the Court enjoined FDA from enforcing
the Pediatric Rule in October 2002, the ANPRM was also rendered obsolete.
As noted above, PREA codified elements of the suspended Pediatric Rule and attempted to fill
gaps left by the Pediatric Rule's suspension.
Table of Contents
- OVERVIEW — REQUIREMENTS OF PREA
- PREA Statutory Requirements
PREA requires all applications (or supplements to an application) submitted under section 505 of
the Act (21 U.S.C. 355) or section 351 of the Public Health Service Act (PHSA) (42 U.S.C. 262)
for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route
of administration to contain a pediatric assessment unless the applicant has obtained a waiver or
deferral (section 505B(a) of the Act). It also authorizes FDA to require holders of approved
NDAs and BLAs for marketed drugs and biological products to conduct pediatric studies under
certain circumstances (section 505B(b) of the Act).
In general, PREA applies only to those drugs and biological products developed for diseases
and/or conditions that occur in both the adult and pediatric populations. Products intended for
pediatric-specific indications will be subject to the requirements of PREA only if they are
initially developed for a subset of the relevant pediatric population.
- Scope of Requirements
- Applications Affected by PREA
Because section 4(b) of PREA makes the legislation retroactive, all approved applications for
new active ingredients, new indications, new dosage forms, new dosing regimens, and new
routes of administration submitted on or after April 1, 1999 (including those approved when the
Pediatric Rule was suspended), are subject to PREA. Under PREA, holders of such approved
applications that did not previously include pediatric assessments, waivers, or deferrals must
submit their pediatric assessments or requests for waiver or deferral (section 4(b)(2)(B) of
PREA). If a waiver request is denied and/or studies are deferred, FDA will require the
applicable studies as postmarketing studies. (For additional information on applicable deferral
dates, see section IV.B and Attachment C.)
- Orphan Drugs
PREA states, "Unless the Secretary requires otherwise by regulation, this section does not apply
to any drug for an indication for which orphan designation has been granted under section 526."6 FDA has not issued regulations applying PREA to orphan-designated indications. Thus,
submission of a pediatric assessment is not required for an application to market a product for an
orphan-designated indication, and waivers are not needed at this time. However, if only one
indication for a product has orphan designation, a pediatric assessment may still be required for
any applications to market that same product for the non-orphan indication(s).
- Generic Drugs Under 505(j) of the Act (21 U.S.C. 355(j))
Because PREA applies only to applications (or supplements to applications) for a new active
ingredient, new indication, new dosage form, new dosing regimen, or new route of
administration, and because an abbreviated new drug application (ANDA) submitted under
section 505(j) of the Act for a duplicate version of a previously approved drug product does not
involve such changes, PREA does not impose pediatric assessment requirements on ANDAs for
generic drugs. However, ANDAs submitted under an approved suitability petition under section
505(j)(2)(C) of the Act for changes in dosage form, route of administration, or new active
ingredient in combination products are subject to the pediatric assessment requirements that
PREA imposes. If clinical studies are required under PREA for a product submitted under an
approved suitability petition and a waiver is not granted, that application is no longer eligible for
approval under an ANDA.
Because PREA is retroactive, all approved and pending ANDAs submitted on or after April 1,
1999 (when the Pediatric Rule became effective) and prior to December 3, 2003 (when PREA
was enacted) under suitability petitions for changes in dosage form, route of administration, or
active ingredient in combination products are subject to PREA. Although some ANDAs
submitted under suitability petitions after April 1, 1999, and prior to December 3, 2003, would
not have been approved as ANDAs had PREA been in effect at the time of approval, PREA's
retroactivity does not require FDA to revoke those previous approvals. Instead, as with NDAs
and BLAs, holders of approved and pending ANDAs submitted under suitability petitions
between April 1, 1999 and December 3, 2003, who have not already obtained waivers, must
submit postapproval pediatric studies or a request for a waiver or deferral of the pediatric
assessment requirement (section 505B(a)(2) of the Act). If a waiver request is denied for a
product already submitted or approved in an ANDA based upon a suitability petition during this
time frame, FDA will require the applicable studies as postmarketing studies.
Table of Contents
- THE PEDIATRIC ASSESSMENT
- What Is the Pediatric Assessment? (Section 505B(a)(2) of the Act)
Under PREA, the pediatric assessment contains data gathered from pediatric studies using
appropriate formulations for each age group for which the assessment is required, and other data
that are adequate to:
- Assess the safety and effectiveness of the drug or the biological product for the claimed
indications in all relevant pediatric subpopulations
- Support dosing and administration for each pediatric subpopulation for which the drug or the
biological product has been assessed to be safe and effective
- When to Submit the Pediatric Assessment in Compliance with PREA
Under PREA, a pediatric assessment must be submitted at the time an application for a new
active ingredient, new indication, new dosage form, new dosing regimen, or new route of
administration is submitted to the Agency, unless the requirement for the assessment has been
deferred or waived. If a deferral has been granted, the pediatric assessment will be due on or
before the date specified by the Agency (section 505B(a)(3) of the Act).
As noted above, PREA is retroactive and requires pediatric assessments for all applications
submitted between April 1, 1999, and the present. To address potential gaps in pediatric
information for applications approved between April 1, 1999, and the present resulting from,
among other things, the suspension of the Pediatric Rule in October 2002, PREA provides for
waivers or deferrals in cases where pediatric study requirements were never addressed and for
extensions of certain deferrals issued previously under the Pediatric Rule (see Attachment C for a
chart of deferral dates under PREA).
If an application previously was granted a waiver of pediatric studies under the Pediatric Rule,
the waiver will continue to apply under PREA (section 4(b)(2)(A) of PREA).
- What Types of Data Are Submitted as Part of the Pediatric Assessment?
The data submitted under PREA will depend on the nature of the application, what is known
about the product in pediatric populations, and the underlying disease or condition being treated.
PREA does not require applicants to conduct separate safety and effectiveness studies in
pediatric patients in every case. PREA states:
If extrapolation from adult effectiveness data is inappropriate, adequate and wellcontrolled
efficacy studies in the pediatric population may nevertheless be required.
Additional information, such as dosing and safety data, could also be important to
support pediatric labeling decisions.
PREA further provides, "A study may not be needed in each pediatric age group if data from one
age group can be extrapolated to another age group" (section 505B(a)(2)(B)(ii) of the Act).
Whether or not pediatric studies in more than one age group are necessary depends on expected
therapeutic benefit and use in each age group, and on whether safety and effectiveness data from
one age group can be extrapolated to other age groups. As with the use of adult data, the
extrapolation may be supplemented with data to define dosing and safety for the relevant age
groups.
Applicants should contact the appropriate review division to discuss the types of pediatric studies
needed to complete their pediatric assessments.
Table of Contents
- THE PEDIATRIC PLAN AND SUBMISSIONS
- When to Develop a Pediatric Plan
A Pediatric Plan is a statement of intent that outlines the pediatric studies (e.g.,
pharmacokinetics/pharmacodynamics, safety, efficacy) that the applicant plans to conduct. The
plan should also address the development of an age-appropriate formulation. Furthermore, it
should address whether and, if so, under what grounds, the applicant plans to request a waiver or
deferral under PREA. Applicants are encouraged to submit their pediatric plans to the Agency as
early as possible in the drug development process and to discuss these plans with the Agency at
critical points in the development process for a particular drug or biologic.
Early consultation and discussions are particularly important for products intended for lifethreatening
or severely debilitating illnesses. For these products, FDA encourages applicants to
discuss the pediatric plan at pre-investigational new drug (pre-IND) meetings and end-of-phase 1
meetings. For products for life-threatening diseases, the review division will provide its best
judgment at the end-of-phase 1 meetings on whether pediatric studies will be required under
PREA and, if so, whether the submission will be deferred until after approval. In general, studies
of drugs or biological products for diseases that are life-threatening or severely debilitating in
pediatric patients and that lack adequate therapy could begin earlier than studies of other
products because the urgency of the need for the products may justify early trials despite the
relative lack of safety and effectiveness information.
For products that are not intended for treatment of life-threatening or severely debilitating
illnesses, applicants are encouraged to submit and discuss the pediatric plan no later than the
end-of-phase 2 meeting. Information to support any planned request for a waiver or deferral of
pediatric studies also should be submitted as part of the background package for this meeting.
The review division will provide its best judgment about (1) the pediatric assessment that will be
required for the product, (2) whether its submission can be deferred, and (3) if deferred, the date
studies will be due. In addition, if relevant, FDA encourages applicants to include a discussion
of their intent to qualify for and the studies needed to earn pediatric exclusivity (see section VIII
for a discussion of PREA and pediatric exclusivity).
When a decision to waive or defer pediatric studies is made at key meetings, the minutes from
those meetings reflecting the decision generally will be provided to applicants for their records.
Alternatively, a separate letter may be sent to the applicant conveying FDA’s decision to either
waive or defer the pediatric assessment. If a deferral of studies is granted at the time of the
meeting, a due date for submission generally will also be included in the meeting minutes or
separate letter.
- What Ages to Cover in a Pediatric Plan
PREA requires, unless waived or deferred, the submission of a pediatric assessment for certain
applications for the claimed indications in all relevant pediatric populations. As discussed in
section VI, PREA authorized FDA to waive assessments when: 1) the drug or biological product
does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients
and 2) is not likely to be used in a substantial number of pediatric patients (section
505B(a)(4)(A)(iii) of the Act). Thus, PREA requires the pediatric assessment to evaluate safety
and effectiveness for the claimed indication(s) for each age group in which the drug or biological
product is expected to provide a meaningful therapeutic benefit over existing therapies for
pediatric patients or is likely to be used in a substantial number7 of pediatric patients.
Under PREA, a drug or biological product is considered to represent a meaningful therapeutic
benefit over existing therapies if FDA estimates that (1) “if approved, the drug or biological
product would represent a significant improvement in the treatment, diagnosis, or prevention of a
disease, compared with marketed products adequately labeled for that use in the relevant
pediatric population,” or (2) “the drug or biological product is in a class of products or for an
indication for which there is a need for additional options” (section 505B(c) of the Act).
Improvement over marketed products might be demonstrated by showing (1) evidence of
increased effectiveness in treatment, prevention, or diagnosis of disease; (2) elimination or
substantial reduction of a treatment-limiting drug reaction; (3) enhancement of compliance; or
(4) safety and effectiveness in a new subpopulation for which marketed products are not
currently labeled.
The BPCA defines "pediatric studies" or "studies" to include studies in all "pediatric age groups
(including neonates in appropriate cases)" in which a drug is anticipated to be used (section
505A(a) of the Act. For purposes of satisfying the requirements of PREA, the appropriate age
ranges to be studied may vary, depending on the pharmacology of the drug or biological product,
the manifestations of the disease in various age groups, and the ability to measure the response to
therapy. In general, however, the pediatric population includes patients age "birth to 16 years,
including age groups often called neonates, infants, children, and adolescents" (21 CFR
201.57(f)(9)).
The complex medical state of neonates and infants makes it critical to evaluate drugs specifically
for their use. The Agency is also aware that trials in neonates and infants pose special ethical
issues. FDA generally will require studies in neonates and infants under PREA if the drug
represents an important advancement and use in these age groups for the approved indication is
anticipated. However, it is possible that partial waivers for these specific age groups might be
appropriate under certain circumstances when "necessary studies are impossible or highly
impracticable," or when "there is evidence strongly suggesting that the drug or biologic product
would be ineffective or unsafe in that age group" (section 505B(a)(4)(B)(i) and (ii) of the Act).
- Must the Sponsor Develop a Pediatric Formulation?
PREA requires pediatric assessments to be gathered "using appropriate formulations for each age
group for which the assessment is required" (section 505B(a)(2)(A) of the Act). Under PREA,
applicants must submit requests for approval of the pediatric formulation used in their pediatric
studies, and failure to submit such a request may render the product misbranded (section 505B(d)
of the Act). FDA interprets the language "request for approval of a pediatric formulation" to
mean that applicants must submit an application or supplemental application for any not
previously approved formulation(s) used to conduct their pediatric studies. Where appropriate,
applicants may need to begin the development of a pediatric formulation before initiation of
pediatric clinical trials.
PREA does, however, specifically authorize FDA to waive the requirement for pediatric studies
in one or more age groups requiring a pediatric formulation if the applicant certifies and FDA
finds that "the applicant can demonstrate that reasonable attempts to produce a pediatric
formulation necessary for that age group have failed" (section 505B(a)(4)(B)(iv) of the Act).
This exception is limited to the pediatric groups requiring that formulation (section
505B(a)(4)(C). FDA believes that this partial waiver provision will generally apply to situations
where the applicant can demonstrate that unusually difficult technological problems prevented
the development of a pediatric formulation. In certain cases, the Agency may seek appropriate
external expert opinion (e.g., from an advisory committee) to assess whether a waiver should be
granted (see section VI.A and B for more detailed information on waivers).
- When to Initiate Pediatric Studies
As discussed in section V.A, applicants may initiate pediatric studies of drugs and biologics for
life-threatening diseases for which adequate treatment is not available earlier in development
than might occur for less serious diseases. The medical need for these products may justify early
pediatric trials despite a relative lack of safety and effectiveness data. In some cases, pediatric
studies of a drug or biological product for a life-threatening disease may begin as early as phase
1 or phase 2, when the initial safety data in adults become available.
The Agency recognizes that in certain cases scientific and ethical considerations will dictate that
pediatric studies should not begin until after approval of the drug or biological product for use by
adults — for example, where a product has not shown any benefit over other adequately labeled
products in the class, the therapeutic benefit is likely to be low, or the risks of exposing pediatric
patients to the new product may not be justified until after the product’s safety profile is well
established in adults after initial marketing.
The Agency recommends that for products with a narrow therapeutic index, the nature of the
disease in the pediatric population to be studied and the context in which the drug will be used
should factor into the decision on when to initiate the studies in the affected pediatric patient
population. For example, studies for an oncology drug product with a narrow therapeutic index
might be conducted in children with a life-threatening cancer at an earlier stage in the drug
development process than studies for a new aminoglycoside antimicrobial used to treat acute
pyelonephritis infections in children. In the latter case, there are several therapeutic options
available, so the investigational drug would likely be studied in children after the approval in
adults for this condition.
- What Information Must Be Submitted to FDA
Pediatric studies of drugs conducted under an investigational new drug application (IND) are
subject to the rules governing INDs, including the content and format requirements of 21 CFR
312.23 and the IND safety and annual reporting requirements described in 21 CFR 312.32 and
312.33, respectively.
- When study reports are submitted as part of an application or supplement to an application,
the content and format must meet the relevant general requirements for submission (see 21
CFR 314.50 for NDA requirements and 21 CFR 601.2 for BLA requirements).
14.50 for NDA requirements and 21 CFR 601.2 for BLA requirements).
Table of Contents
- WAIVERS AND DEFERRALS
- What Is a Waiver?
PREA authorizes FDA to waive the requirement to submit the pediatric assessment, based on
established criteria, for some or all pediatric age groups. FDA can grant a full or partial waiver
of the requirements on its own initiative or at the request of an applicant. If an applicant requests
a waiver, the applicant should provide written justification for the waiver and evidence to
support the request.
- How to Apply for a Waiver
- Criteria for Full Waiver (Section 505B(a)(4)(A) of the Act)
On FDA’s initiative or at the request of an applicant, FDA will grant a full waiver of the
requirement to submit pediatric assessments if the applicant certifies and FDA finds one or more
of the following:
- Necessary studies are impossible or highly impracticable (because, for example,
the number of patients is so small or the patients are geographically dispersed) (section
505B(a)(4)(A)(i) of the Act).
Another example is a drug or biological product for an indication that has extremely
limited applicability to pediatric patients because the pathophysiology of these diseases
occur for the most part in the adult population. FDA would be likely to grant a waiver
for studies on products developed for the treatment of these conditions without requiring
applicants to provide additional evidence of impossibility or impracticality. For a list of
adult-related conditions that may be candidates for a disease-specific waiver, see
Attachment A, Sample Waiver Request Form.
- There is evidence strongly suggesting that the drug or biological product would be
ineffective or unsafe in all pediatric age groups (section 505B(a)(4)(A)(ii) of the Act).
If a waiver is granted based upon evidence that the drug is unsafe or ineffective in
pediatric populations, the applicant must include this information in the labeling for the
drug or biological product (section 505B(a)(4)(D) of the Act).
- The drug or biological product (1) does not represent a meaningful therapeutic
benefit over existing therapies for pediatric patients, and (2) is not likely to be used in a
substantial number of pediatric patients (section 505B(a)(4)(A)(iii) of the Act).
- Criteria for Partial Waiver (Section 505B(a)(4)(B) of the Act)
On its own initiative or at the request of an applicant, FDA will grant a partial waiver of the
requirement to submit pediatric assessments for a drug or biological product with respect to a
specific pediatric age group, if the applicant certifies and FDA finds evidence of one or more of
the following:
- Necessary studies are impossible or highly impracticable (because, for example,
the number of patients in that age group is so small or patients in that age group are
geographically dispersed) (section 505B(a)(4)(B)(i) of the Act).
- There is evidence strongly suggesting that the drug or biological product would be
ineffective or unsafe in that age group (section 505B(a)(4)(B)(ii) of the Act). If a partial
waiver is granted based on evidence that the drug is unsafe or ineffective in pediatric
populations, the applicant must include this information in the labeling for the drug or
biological product (section 505B(a)(4)(D) of the Act).
- The drug or biological product (1) does not represent a meaningful therapeutic
benefit over existing therapies for pediatric patients in that age group and (2) is not likely
to be used by a substantial number of pediatric patients in that age group (section
505B(a)(4)(B)(iii) of the Act).
- The applicant can demonstrate that reasonable attempts to produce a pediatric
formulation for that age group have failed (section 505B(a)(4)(B)(iv) of the Act). If a
waiver is granted on the basis that it is not possible to develop a pediatric formulation, the
waiver shall cover only the pediatric groups requiring that formulation (section
505B(a)(4)(C) of the Act).
- Information in a Waiver Request
As noted in section V, discussions with FDA on developing pediatric plans and initiating
pediatric studies should occur early in the drug development process. If an applicant believes a
full or partial waiver of the pediatric studies requirement is warranted, FDA strongly encourages
the applicant to request the waiver at the earliest appropriate time. This guidance includes a
sample Waiver Request to assist applicants in providing sufficient information for FDA to
determine whether to grant a waiver request (Attachment A). However, the information
necessary to support any particular waiver will be determined on a case-by-case basis.
To request a waiver, we recommend an applicant provide:
- Product name, applicant name, and indication
- Age group(s) included in waiver request
- Statutory reason(s) for requesting a waiver, including reference to the applicable statutory
authority (i.e., one of 2(a)-(d) in Attachment A)
- Evidence that the request meets the statutory reason(s) for waiver of pediatric assessment
requirements
- Applicant Certification
- Waiver Decision
The Agency will grant a waiver request if FDA determines that any of the criteria for a waiver
enumerated in the statute have been met. As noted above, if a full or partial waiver is granted
"because there is evidence that a drug or biological product would be ineffective or unsafe in
pediatric populations, this information shall be included in the labeling for the drug or biological
product" (section 505B(a)(4)(D) of the Act).
As discussed in section V, for waivers agreed to at the end-of-phase 2 meetings, the meeting
minutes will document the waiver of pediatric assessment requirements. Full or partial waiver
documentation (meeting minutes or a letter from FDA) should be submitted in the Clinical Data
Section of the NDA or BLA and noted in Form FDA-356h under the "Pediatric Use" part of item
8, and also under item 20, "Other." Under "Other," the applicant should identify the location
(volume and page number) of the waiver documentation in the NDA or BLA submission.
Decisions to waive the requirement for submission of pediatric assessments that are made early
in the pre-approval development period (e.g., end-of-phase 1 or end-of-phase 2 meetings) reflect
the Agency’s best judgment at that time. If, prior to approval, the Agency becomes aware of
new or additional scientific information that affects the criteria on which the waiver decision was
based, the Agency may reconsider its earlier decision. A waiver decision becomes final once
issued in the approval letter for an NDA, BLA, or supplement.
- What Is a Deferral?
A deferral acknowledges that a pediatric assessment is required, but permits the applicant to
submit the pediatric assessment after the submission of an NDA, BLA, or supplemental NDA or
BLA. On its own initiative or at the request of an applicant, FDA may defer the submission of
some or all of the pediatric studies until a specified date after approval of the drug or issuance of
the license for a biological product for adult use (section 505B(a)(3) of the Act).
- How to Apply for a Deferral
- Criteria for Deferral (Section 505B(a)(3) of the Act)
FDA may defer the timing of submission of some or all required pediatric studies if it finds one
or more of the following:
- The drug or biological product is ready for approval for use in adults before pediatric studies
are complete (section 505B(a)(3)(A)(i) of the Act).
- Pediatric studies should be delayed until additional safety or effectiveness data have been
collected (section 505B(a)(3)(A)(ii) of the Act).
OR
- There is another appropriate reason for deferral (section 505B(a)(3)(A)(iii) of the Act) (e.g.,
development of a pediatric formulation is not complete).
In addition, to obtain a deferral the applicant must submit certification of the reason(s) for
deferring the assessments, a description of the planned or ongoing studies, and evidence that the
studies are being conducted or will be conducted with due diligence and at the earliest possible
time (section 505B(a)(3)(B)(i)-(iii) of the Act).
- Information in a Deferral Request
FDA has provided a sample Deferral Request checklist to assist applicants in providing sufficient
information for FDA to determine whether to grant a deferral request (Attachment B). To
request a deferral, we recommend an applicant provide:
- Product name, applicant name, and indication
- Age group(s) included in deferral request
- Where deferral is only requested for certain age groups, reason(s) for not including entire
pediatric population in deferral request (e.g., studies have already been completed in other
age groups and need not be deferred)
- Reason(s) for requesting a deferral
- Evidence justifying that the proposed product meets the criteria for deferral of the pediatric
assessment requirement
- Description of planned or ongoing studies
- Evidence that planned or ongoing studies are proceeding
- Projected date for the submission of the pediatric assessment (deferral date)
- Applicant certification
- Deferral Decision
The decision to defer and the deferral date will be determined on a case-by-case basis.
Considerations used in determining whether and how long to defer submission of the pediatric
assessment may include:
- The need for the drug or biologic in pediatric patients
- Availability of sufficient safety data to initiate pediatric trials
- The nature and extent of pediatric data needed to support pediatric labeling
- The existence of substantiated difficulties in enrolling patients
- Evidence of technical problems in developing pediatric formulations
As discussed in section V.A, the meeting minutes or a separate letter will document the deferral
of pediatric assessments agreed to at the end-of-phase 2 meetings. For a deferral granted during
the pre-approval development period, it is possible that FDA may reevaluate the length of the
deferral closer to the time of approval, taking into account any new information obtained while
the product was in development and information reviewed in the NDA or BLA. The pediatric
assessments deferred under PREA are required postmarketing studies subject to the annual status
reporting and information disclosure provisions of 21 CFR 314.81(b)(2)(vii)(a) and (b) and 21
CFR 601.70.
Table of Contents
- COMPLIANCE WITH PREA
If a pediatric assessment or a request for approval of a pediatric formulation is not submitted by
an applicant in accordance with the statutory requirements, the drug or biological product may be
considered misbranded solely because of that failure and subject to relevant enforcement action
(section 505B(d)(1) of the Act). The failure to submit a pediatric assessment or request for
waiver or deferral will not be the basis for withdrawing approval of a drug under section 505(e)
of the Act or the revocation of a license for a biological product under section 351 of the PHSA
(section 505B(d)(2) of the Act). However, the Agency could bring injunction or seizure
proceedings if a product is found to be misbranded under these provisions.8
Table of Contents
- PREA AND PEDIATRIC EXCLUSIVITY
It is the Agency’s policy to offer applicants the opportunity to qualify for pediatric exclusivity
under section 505A of the Act for studies required and conducted under PREA. Under that
policy, however, FDA will not issue a Written Request for or grant pediatric exclusivity for
studies that have been submitted to the Agency before the Written Request is issued. Therefore,
an applicant seeking to qualify for pediatric exclusivity should obtain a Written Request for
studies from FDA before submitting the pediatric studies to satisfy PREA. (Note that for
marketed drugs and biological products, the Agency is required to issue a Written Request prior
to requiring studies under PREA (section 505B(b)(3) of the Act)). To qualify for pediatric
exclusivity, the pediatric studies conducted to satisfy the requirements of PREA must also satisfy
all of the requirements for pediatric exclusivity under section 505A of the Act (see sections
505A(d) and 505A(h) of the Act).
In addition, there is a noteworthy distinction between the scope of the studies requested under the
pediatric exclusivity provisions and what is required under PREA. For pediatric exclusivity
under the Act, FDA's authority to issue a Written Request extends to the use of an active moiety
for all indications that occur in the pediatric population, regardless of whether the indications
have been previously approved in adults or approval for those indications is being sought in
adults (see section 505A(a), which refers only to "information relating to the use of a new drug
in the pediatric population"). Under PREA, on the other hand, a pediatric assessment is required
only on those indications included in the pending application (section 505B(a), which addresses
"the safety and effectiveness of the drug or biological product for the claimed indications"). To
learn more about eligibility for pediatric exclusivity, applicants should consult the guidance for
industry entitled Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food,
Drug, and Cosmetic Act9 or should contact the relevant review division.
Table of Contents
- ADDITIONAL INFORMATION
- Additional Information Concerning PREA
General information about complying with PREA can be obtained from the Division of Pediatric
Drug Development (DPDD), 301-594-7337 or 301-827-7777, e-mail pdit@cder.fda.gov.
Additional pediatric information is available at http://www.fda.gov/cder/pediatric/index.htm. Specific information about the types of pediatric studies that must be conducted and requirements for submission of assessments for your drug product can be obtained from the
appropriate review division.
- Additional Information Concerning Pediatric Exclusivity
General information and the latest statistical information regarding pediatric exclusivity are
located at http://www.fda.gov/cder/pediatric/index.htm. You can also refer to the guidance for industry on Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act.
Table of Contents
ATTACHMENT A — SAMPLE WAIVER REQUEST
Product name:
IND/NDA/BLA number (as applicable):
Applicant:
Indications(s):
(NOTE: If drug is approved for or you are seeking approval for more than one indication,
address the following for each indication.)
- Identify pediatric age group(s) included in your waiver request.
- With regard to each age group for which a waiver is sought, state the reason(s) for
waiving pediatric assessment requirements with reference to applicable statutory
authority (i.e., one of the options (a)-(d) listed below — choose all that apply):
- Studies are impossible or highly impractical (because, for example, the number of
pediatric patients is so small or geographically dispersed). If applicable, please
check from the following list of adult-related conditions that may qualify the drug
product for disease-specific waivers:
___ Age-related macular degeneration
___ Alzheimer’s disease
___ Amyotrophic lateral sclerosis
___ Arteriosclerosis
___ Infertility
___ Menopause symptoms
___ Osteoarthritis
___ Parkinson’s disease
___ Other (please state and justify)
|
___ Basal cell and squamous cell cancer
___ Breast cancer
___ Colorectal cancer
___ Endometrial cancer
___ Hairy cell cancer
___ Lung cancer (small cell and non-small cell)
___ Oropharynx cancers (squamous cell)
___ Ovarian cancer (non-germ cell)
___ Pancreatic cancer
___ Prostate cancer
___ Renal cell cancer
___ Uterine cancer
|
- The product would be ineffective or unsafe in one or more of the pediatric age
group(s) for which a waiver is being requested.
- The product fails to represent a meaningful therapeutic benefit over existing
therapies for pediatric patients and is unlikely to be used in a substantial number
of all pediatric age groups or the pediatric age group(s) for which a waiver is
being requested.
- Reasonable attempts to produce a pediatric formulation for one or more of the
pediatric age group(s) for which the waiver is being requested have failed. Please
document previous attempts to make a pediatric formulation and describe reasons
for failure.
- Provide evidence that the statutory reason(s) for waiver of pediatric studies have been
met (not necessary if a 2(a) category is checked).
- Applicant certification.
Table of Contents
ATTACHMENT B — SAMPLE DEFERRAL REQUEST
Product name:
IND/NDA/BLA number (as applicable):
Applicant:
Indications(s):
(NOTE: If drug is approved for or you are seeking approval for more than one indication,
address the following for each indication.)
- What pediatric age group(s) are included in your deferral request?
- Reason(s) for requesting deferral of pediatric studies (address each age group separately
and for each age group — choose all that apply):
- Adult studies completed and ready for approval
- Additional postmarketing safety data needed (describe)
- Nature and extent of pediatric data needed (explain)
- Evidence provided of technological problems with development of a pediatric
formulation
- Difficulty in enrolling pediatric patients (provide documentation)
- Other (specify)
- What pediatric age group(s) is/are not included in your deferral request?
- Reason(s) for not including the pediatric age group(s) listed in number 3 in the deferral
request (address each excluded age group separately and for each such age group —
choose all that apply):
- Adequate pediatric labeling exists
- Studies completed in the specified age group
- Requesting a waiver
- Currently conducting pediatric studies that will be submitted with application
- Other (specify)
- Has a pediatric plan been submitted to the Agency?
- If so, provide date submitted.
- If not, provide projected date pediatric plan is to be submitted.
- Suggested deferred date for submission of studies.
Table of Contents
ATTACHMENT C — COMPLIANCE DATES FOR APPLICATIONS SUBJECT TO PREA
Categories of Application |
Expected Date of Compliance |
Application or supplement submitted between 4/1/99 and 12/3/03, no waiver or
deferral was granted and no studies were submitted |
Immediate unless FDA specifies later date |
Application or supplement submitted between 4/1/99 and 10/17/02, studies were
deferred to a date after 4/1/99, but no studies were submitted |
Deferral date + 411 days |
Application or supplement submitted between 10/17/02 and 12/3/03 and
approved after 12/3/03, studies were deferred |
Immediate unless later date is specified in deferral letter |
Applications submitted after 12/3/03, studies were deferred |
Date specified in deferral letter |
The dates in the chart are relevant as follows:
4/1/99 The date the Pediatric Rule became effective
10/17/02 The date that implementation and enforcement of the Pediatric Rule was
suspended by court order
12/3/03 The date that PREA was enacted
Table of Contents
1
This guidance has been prepared by the PREA Working Group at the Food and Drug Administration (FDA).
2
For purposes of this guidance, references to "drugs" and "drug and biological products" includes drugs approved
under section 505 of the Act (21 U.S.C. 355) and biological products licensed under 351 of the Public Health
Service Act (PHSA) (42 U.S.C. 262) that are drugs.
Paperwork Reduction Act Public Burden Statement: According to the Paperwork Reduction Act of 1995, a
collection of information should display a valid OMB control number. The draft guidance contains information
collections approved in OMB Nos. 0910-0001 (expires May 31, 2008) and 1910-0433 (expires March 31, 2007). In
addition, the time required to complete this information collection is estimated to average from 8 to 50 hours per
response, including the time to prepare and submit an application containing required studies or request a waiver
from such studies.
3
For purposes of this guidance, the term "pediatric assessment" describes the required submissions under PREA that
contain data, primarily from required pediatric clinical studies, that are adequate to assess safety and effectiveness
and support dosing and administration for claimed indications in all relevant pediatric populations (section
505B(a)(1) and (2) of the Act). Generally, the terms "pediatric assessment" and "pediatric studies" are used
interchangeably.
4
The Pediatric Rule was codified at 21 CFR 314.55 and 601.27, with additional amendments to 21 CFR 201, 312,
314, and 601.
5
FDA issues Written Requests for pediatric studies under 21 U.S.C. 355a.
6
Section 526 is codified at 21 U.S.C. 360bb.
7
PREA does not define a "substantial number." In the past, FDA generally has considered 50,000 patients to be a
substantial number of patients (see, for example, October 27, 1997, DHHS Public Meeting on FDA’s Proposed
Regulations to Increase Pediatric Use Information for Drugs and Biologics). The Agency, however, will take into
consideration the nature and severity of the condition in determining whether a drug or biological product will be
used in a substantial number of pediatric patients.
8
See section 302 of the Act (21 U.S.C. 332), Injunction Proceedings; section 304 of the Act (21 U.S.C. 334),
Seizure.
9
Available on the Internet at http://www.fda.gov/cder/guidance/index.htm.
|