Guidance for Industry 
 
 
 
How to Comply with the Pediatric 
Research Equity Act 
 
 
DRAFT GUIDANCE 
 
 
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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.  
 
 
 
 
 
 
 
 
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
 
 
   
Guidance for Industry 
 
 
 
How to Comply with the Pediatric 
Research Equity Act 
 
 
 
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 
 
 
I.  INTRODUCTION...............................................................................................................................1 
II.  BACKGROUND.................................................................................................................................2 
III.  OVERVIEW  REQUIREMENTS OF PREA...............................................................................3 
A.  PREA STATUTORY REQUIREMENTS.................................................................................................3 
B.  SCOPE OF REQUIREMENTS.................................................................................................................3 
IV.  THE PEDIATRIC ASSESSMENT...................................................................................................5 
A.  WHAT IS THE PEDIATRIC ASSESSMENT? (SECTION 505B(A)(2) OF THE ACT)...................................5 
B.  WHEN TO SUBMIT THE PEDIATRIC ASSESSMENT IN COMPLIANCE WITH PREA................................5 
C.  WHAT TYPES OF DATA ARE SUBMITTED AS PART OF THE PEDIATRIC ASSESSMENT?.......................5 
V.  THE PEDIATRIC PLAN AND SUBMISSIONS.............................................................................6 
A.  WHEN TO DEVELOP A PEDIATRIC PLAN............................................................................................6 
B.  WHAT AGES TO COVER IN A PEDIATRIC PLAN..................................................................................7 
C.  MUST A PEDIATRIC FORMULATION BE DEVELOPED?........................................................................8 
D.  WHEN TO INITIATE PEDIATRIC STUDIES...........................................................................................9 
E.  WHAT INFORMATION SHOULD BE SUBMITTED TO FDA...................................................................9 
VI.  WAIVERS AND DEFERRALS.........................................................................................................9 
A.  WHAT IS A WAIVER?........................................................................................................................9 
B.  HOW TO APPLY FOR A WAIVER.......................................................................................................10 
C.  WHAT IS A DEFERRAL?...................................................................................................................12 
D.  HOW TO APPLY FOR A DEFERRAL...................................................................................................12 
VII.  COMPLIANCE WITH PREA....................................................................................................14 
VIII.  PREA AND PEDIATRIC EXCLUSIVITY...............................................................................14 
IX.  ADDITIONAL INFORMATION....................................................................................................15 
A.  ADDITIONAL INFORMATION CONCERNING PREA...........................................................................15 
B.  ADDITIONAL INFORMATION CONCERNING PEDIATRIC EXCLUSIVITY..............................................15 
ATTACHMENT A  SAMPLE WAIVER REQUEST.........................................................................16 
ATTACHMENT B  SAMPLE DEFERRAL REQUEST....................................................................17 
ATTACHMENT C  COMPLIANCE DATES FOR APPLICATIONS SUBJECT TO PREA........18 
 
 
 
 
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GUIDANCE FOR INDUSTRY1 
 
How to Comply with the Pediatric Research Equity Act 
 
 
 
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. 
 
 
 
I.  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). 
 
                                                 
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. 
 
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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.  
 
II.  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. 
 
                                                 
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. 
 
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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.  
 
III.  OVERVIEW  REQUIREMENTS OF PREA  
 
A.  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. 
 
B.  Scope of Requirements 
 
1.  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 
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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.)  
 
2.  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). 
 
3.  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. 
                                                 
6 Section 526 is codified at 21 U.S.C. 360bb. 
 
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IV.  THE PEDIATRIC ASSESSMENT 
 
A.  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 
 
B.  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). 
 
C.  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 the course of the disease and the effects of the drug are sufficiently similar in 
adults and pediatric patients, the Secretary may conclude that pediatric 
effectiveness can be extrapolated from adequate and well-controlled studies in 
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adults, usually supplemented with other information obtained in pediatric patients, 
such as pharmacokinetic studies.  
 
(Section 505B(a)(2)(B)(i) of the Act.) 
 
If extrapolation from adult effectiveness data is inappropriate, adequate and well-
controlled 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. 
 
V.  THE PEDIATRIC PLAN AND SUBMISSIONS 
 
A.  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 life-
threatening 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. 
 
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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 FDAs 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. 
 
B.  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 
                                                 
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 FDAs 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. 
 
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(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). 
 
C.  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).     
 
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D.  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 products 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.  
 
E.  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). 
 
VI.  WAIVERS AND DEFERRALS 
 
A.  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 
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a waiver, the applicant should provide written justification for the waiver and evidence to 
support the request. 
 
B.  How to Apply for a Waiver 
 
1.  Criteria for Full Waiver (Section 505B(a)(4)(A) of the Act) 
 
On FDAs 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:  
 
(a)   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. 
 
(b)  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). 
 
(c)  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). 
 
2.  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: 
 
(a)  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).   
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(b)  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). 
 
(c)  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). 
 
(d)  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). 
 
3.  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 
 
4.  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 
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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 Agencys 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. 
 
C.  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). 
 
D.  How to Apply for a Deferral 
 
1.  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). 
 
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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). 
 
2.  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 
 
3.  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 
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reporting and information disclosure provisions of 21 CFR 314.81(b)(2)(vii)(a) and (b) and 21 
CFR 601.70. 
 
VII.  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  
 
VIII.  PREA AND PEDIATRIC EXCLUSIVITY  
 
It is the Agencys 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. 
                                                 
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. 
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IX.  ADDITIONAL INFORMATION 
 
A.  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. 
 
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.   
 
B.  Additional Information Concerning Pediatric Exclusivity 
 
General information and the latest statistical information regarding pediatric exclusivity are 
located at http://www.fda.gov/cder/pediatric.  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.  
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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.) 
 
1.  Identify pediatric age group(s) included in your waiver request. 
 
2.  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): 
(a)  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              Basal cell and squamous cell cancer  
            Alzheimers disease              Breast cancer 
            Amyotrophic lateral sclerosis              Colorectal cancer 
            Arteriosclerosis              Endometrial cancer 
            Infertility              Hairy cell cancer 
             Menopause symptoms               Lung cancer (small cell and non-small cell) 
            Osteoarthritis               Oropharynx cancers (squamous cell) 
            Parkinsons disease              Ovarian cancer (non-germ cell) 
              Pancreatic cancer 
            Other (please state and justify)              Prostate cancer 
              Renal cell cancer 
            Uterine cancer 
(b)  The product would be ineffective or unsafe in one or more of the pediatric age 
group(s) for which a waiver is being requested. 
(c)  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. 
(d)  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. 
 
3.  Provide evidence that the statutory reason(s) for waiver of pediatric studies have been 
met (not necessary if a 2(a) category is checked). 
 
4.  Applicant certification.                                                                                                                                   
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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.) 
 
1.  What pediatric age group(s) are included in your deferral request? 
 
2.  Reason(s) for requesting deferral of pediatric studies (address each age group separately 
and for each age group  choose all that apply): 
 
(a)  Adult studies completed and ready for approval             
(b)  Additional postmarketing safety data needed (describe) 
(c)  Nature and extent of pediatric data needed (explain) 
(d)  Evidence provided of technological problems with development of a pediatric 
formulation   
(e)  Difficulty in enrolling pediatric patients (provide documentation) 
(f)  Other (specify) 
 
3.  What pediatric age group(s) is/are not included in your deferral request?  
 
4.   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): 
 
(a)  Adequate pediatric labeling exists 
(b)  Studies completed in the specified age group 
(c)  Requesting a waiver  
(d)  Currently conducting pediatric studies that will be submitted with application  
(e)   Other (specify) 
 
5.  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. 
 
6.  Suggested deferred date for submission of studies. 
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ATTACHMENT C  COMPLIANCE DATES FOR 
APPLICATIONS SUBJECT TO PREA 
 
 
Categories of Application  Expected Date of Compliance 
 
Application or supplement submitted  Immediate unless FDA specifies later date 
between 4/1/99 and 12/3/03, no waiver or 
deferral was granted and no studies were 
submitted 
 
Application or supplement submitted  Deferral date + 411 days 
between 4/1/99 and 10/17/02, studies were 
deferred to a date after 4/1/99, but no 
studies were submitted 
 
Application or supplement submitted  Immediate unless later date is specified in 
between 10/17/02 and 12/3/03 and  deferral letter 
approved after 12/3/03, studies were 
deferred 
 
Applications submitted after 12/3/03,   Date specified in deferral letter 
studies were deferred 
 
 
 
 
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 
 
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