Q.01

What does the FDA require under PREA?

PREA (FD&C Act section 505B, 21 U.S.C. 355c) requires sponsors of NDAs, BLAs and supplements for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration to submit pediatric assessments with the application. The assessments must show safety and effectiveness in all relevant pediatric subpopulations and support pediatric dosing. Sponsors must also agree an initial Pediatric Study Plan (iPSP) with FDA early in development. FDA may defer or waive the studies, and it can also require studies for drugs already on the market [1].

Approach: I read the 2023 U.S. Code text of 21 U.S.C. 355c, the current eCFR text of 21 CFR 314.55, and FDA's postmarketing requirements and commitments database. The last statutory amendment shown in the 2023 Code is Pub. L. 117-328 (Dec. 29, 2022).

1. What triggers PREA (section 505B(a)(1))

  • Standard trigger: an application or supplement submitted on or after September 27, 2007, under section 505 or PHS Act 351, for any of the five changes listed above. The sponsor "shall submit with the application" the pediatric assessments.
  • Molecularly targeted cancer drugs: an original application for a new active ingredient, submitted on or after the date 3 years after August 18, 2017, must include a molecularly targeted pediatric cancer investigation. This applies if the drug treats an adult cancer and is aimed at a molecular target that FDA finds "substantially relevant" to a pediatric cancer. The study must give data on dosing, safety and preliminary efficacy. FDA must publish lists of targets that trigger this requirement and targets that are automatically waived (subsection (m)).
  • Biosimilars: a non-interchangeable biosimilar is treated as having a new active ingredient, so PREA applies. An interchangeable biosimilar is not (subsection (l)).
  • Orphan exemption: PREA does not apply to an indication with orphan designation, unless FDA requires otherwise by regulation. The exemption does not cover the molecularly targeted cancer investigation (subsection (k)).
  • [1]

2. What the assessment must contain (section 505B(a)(2))

  • The data must be gathered using age-appropriate formulations for each age group where an assessment is required.
  • Extrapolation:
    • FDA may extrapolate pediatric effectiveness from adequate, well-controlled adult studies if the disease and the drug's effects are sufficiently similar in adults and children. Such studies are usually supplemented with pediatric data such as pharmacokinetics.
    • A study may not be needed in every age group if data from one group can be extrapolated to another.
    • The supporting science must be documented in the reviews.
  • [1]

3. Pediatric Study Plan (section 505B(e))

  • When: the iPSP is due before the assessments are submitted, and no later than 60 calendar days after the end-of-Phase 2 meeting (or another time agreed with FDA).
  • What it contains: an outline of the planned studies (objectives, design, age groups, endpoints, statistical approach), any request for a deferral or waiver, and any other information required by regulation.
  • FDA's response: within 90 days of receiving the plan, FDA meets with the sponsor or sends written comments.
  • Agreement: within 90 days after that, the sponsor submits an "Agreed Initial Pediatric Study Plan". FDA confirms it in writing within 30 days.
  • Either side can amend the plan at any time.
  • FDA's internal pediatric review committee under 21 U.S.C. 355d reviews the plans, assessments, deferrals and waivers.
  • [1]

4. Deferrals (section 505B(a)(4))

  • Grounds: the drug is ready for adult approval before pediatric studies are complete; pediatric studies should wait for more safety or effectiveness data; or there is another appropriate reason.
  • What the sponsor submits: a certification of the grounds, the PSP, evidence of due diligence, and a timeline for completing the studies.
  • Extensions: a sponsor must request one at least 90 days before the deferral expires. FDA must respond within 45 days.
  • Annual reporting: every year the sponsor must report study progress (or evidence of due diligence if there has been none), the projected completion date, and why the deferral is still needed. FDA publishes this within 90 days.
  • [1]

5. Waivers (section 505B(a)(5))

FDA "shall grant" a waiver, as appropriate, if the sponsor certifies and FDA finds one of these grounds:

  • Full waiver:
    • studies are impossible or highly impracticable (for example, too few patients or patients too widely dispersed); or
    • there is strong evidence the drug would be ineffective or unsafe in all pediatric age groups; or
    • the drug offers no meaningful therapeutic benefit for children and is unlikely to be used in a substantial number of them.
  • Partial waiver (for a specific age group): the same grounds applied to that age group, plus failed reasonable attempts to make a pediatric formulation. A formulation-based waiver covers only the age groups that need that formulation, and the sponsor's justification is made public.
  • If a waiver is based on the drug being ineffective or unsafe in children, that information must go into the labeling.
  • [1]

6. Marketed products (section 505B(b))

FDA may order, by letter, the holder of an approved NDA or BLA to submit pediatric assessments by a set date in any of three cases:

  • the drug is used in a substantial number of pediatric patients for its labeled indications, and adequate pediatric labeling could benefit them;
  • there is reason to believe it would offer a meaningful therapeutic benefit for children; or
  • the lack of pediatric labeling could pose a risk to children.

Similar waiver grounds apply [1].

7. Non-compliance (section 505B(d))

  • If a sponsor misses a required assessment, investigation, deferral requirement or pediatric formulation request, FDA "shall issue" a non-compliance letter.
  • The sponsor must reply in writing within 45 calendar days. FDA posts the letter and reply 60 days after issuance, with trade secrets redacted.
  • The product "may be considered misbranded" and face enforcement, but not action under section 333 (21 U.S.C. 333).
  • The failure cannot be used to withdraw an NDA approval or revoke a BLA license.
  • [1]

8. Labeling and transparency (sections 505B(g)-(i))

  • FDA "shall order" the labeling to include the assessment results and its determination, including when results are inconclusive.
  • If FDA and the sponsor cannot agree on labeling, the matter goes to the Pediatric Advisory Committee. A sponsor that still refuses may have its drug deemed misbranded.
  • FDA publishes the pediatric reviews within 210 days (priority review) or 330 days (standard review) of submission.
  • Sponsors must send information on labeling changes to health care providers.
  • For 18 months after a pediatric labeling change, all adverse event reports for the drug go to the Office of Pediatric Therapeutics.
  • [1]

9. The regulation: 21 CFR 314.55

  • The rule (63 FR 66670, Dec. 2, 1998) sets the same core requirement for drug applications, using the same five triggers and wording that the application "shall contain" adequate pediatric data.
  • It covers deferral (the sponsor must certify the grounds, describe the studies and show due diligence) and full or partial waivers.
  • It defines "meaningful therapeutic benefit" and exempts orphan-designated indications.
  • It does not contain the later statutory additions: the PSP process, the cancer molecular-target investigation, and the non-compliance letter regime.
  • [2]

10. In practice

FDA's postmarketing requirements and commitments database (2026-07-31 edition) lists more than 700 PMRs classed as "Pediatric Research Equity Act". These are the deferred pediatric studies that FDA tracks after approval [3].

PREA sits alongside the voluntary pediatric exclusivity incentive in section 505A (21 U.S.C. 355a, "Pediatric studies of drugs") [4]. Pediatric device provisions are separate, at 21 U.S.C. 360e-1 [5].

Q.02

How does BPCA pediatric exclusivity differ?

BPCA (FD&C Act section 505A, 21 U.S.C. 355a) is a voluntary incentive, while PREA is a mandate. FDA issues a Written Request for pediatric studies. If the sponsor agrees, completes the studies on time and FDA accepts the reports, the drug gets six more months of exclusivity or patent protection. Sponsors can decline, and no assessment is required by default [4]. Under PREA, by contrast, a sponsor "shall submit" pediatric assessments when its application triggers the requirement [1].

Approach: I read the 2023 U.S. Code text of 21 U.S.C. 355a (last amended by Pub. L. 117-9, Apr. 23, 2021) and compared it with 21 U.S.C. 355c from the previous answer. Unless another citation is shown, everything below comes from section 355a [4].

Side-by-side

PointBPCA (section 505A)PREA (section 505B)
NatureAn incentive: the sponsor chooses to answer a Written RequestA requirement triggered by the application
What starts itFDA decides pediatric information "may produce health benefits" and issues a Written Request (subsections (b), (c), (d)(1))A new active ingredient, indication, dosage form, dosing regimen or route of administration
Scope of studiesAny pediatric use FDA asks about. One Written Request "may include uses that are both approved and unapproved" (subsection (d)(1)(B))Limited to the indication in the application
Who can receive a requestAn IND sponsor, an NDA applicant under 505(b)(1), or the holder of an approved 505(b)(1) NDA (subsection (d)(1)(A))NDA and BLA applicants; FDA can also order studies for marketed products under 505B(b)
Orphan indicationsCan qualify. Orphan exclusivity goes from 7 years to 7 years and 6 monthsExempt for orphan-designated indications, except the cancer molecular-target investigation
RewardSix months added to existing exclusivity and patent protectionNone
If the sponsor doesn't actDeclining is allowed, but reasons must be given. FDA may then switch to PREA (subsection (n))Non-compliance letter, and the product "may be considered misbranded"

What the six months attach to (subsections (b)(1) and (c)(1))

  • New chemical entity exclusivity: 5 years becomes 5 years and 6 months. The related 4-year, 48-month and 7.5-year periods become 4.5 years, 54 months and 8 years.
  • Three-year exclusivity (clauses (iii) and (iv) of 505(c)(3)(E) and 505(j)(5)(F)): becomes 3 years and 6 months.
  • Orphan exclusivity (section 360cc(a)): becomes 7 years and 6 months.
  • Patents:
    • Where the listed patent has a paragraph II or III certification, FDA cannot approve the competing 505(b)(2) or ANDA application until 6 months after the patent expires.
    • For a paragraph IV certification, the 6 months apply only if a court finds the patent valid and infringed.
  • Timing cut-off (subsection (b)(2)): the Secretary "shall not extend" a period if FDA accepts the study reports later than 9 months before that period expires.
  • Limits on repeat awards (subsection (g)):
    • A drug that has already had the six months may get another six months on its 3-year exclusivity for a supplemental application.
    • It may not get another patent extension or another orphan extension.
  • Generic 180-day exclusivity (subsection (m)): if the first ANDA filer's 180-day period overlaps the pediatric six months, the 180-day period is extended by the number of days of overlap.

Process (subsection (d))

  • Contents of the Written Request:
    • It must set a timeframe and ask the sponsor to propose pediatric labeling.
    • It must take into account adequate representation of children of ethnic and racial minorities.
    • If it does not ask for studies in neonates, it must explain why.
  • Sponsor's response: due within 180 days of receiving the request. The sponsor either says when studies will start or declines with reasons. If it declines because a pediatric formulation cannot be developed, it must say why.
  • Proposed requests: FDA must act on a sponsor's Proposed Pediatric Study Request, or on a proposed amendment to a Written Request, within 120 calendar days.
  • Submitting the studies: the sponsor must send all available postmarket adverse event reports together with the study reports.
  • FDA's decision on the reports: within 180 days FDA accepts or rejects them. The only question is whether the studies "fairly respond" to the request, were conducted under accepted scientific principles, and were reported as filing rules require.
  • Notice: FDA publishes a notice of the exclusivity decision, with the Written Request attached, within 30 days. If an approved pediatric formulation is not marketed within one year, FDA publishes a notice naming the drug.
  • Internal review: the internal review committee under 21 U.S.C. 355d reviews every Written Request before it is issued.

How the two programmes interact

  • One set of studies can serve both: "Written requests under this section may consist of a study or studies required under section 355c" (subsection (h)). The six months are granted "only" for studies that were the subject of a Written Request and whose reports FDA accepted.
  • If studies aren't submitted or the sponsor declines (subsection (n)): where FDA's pediatric committee finds a continuing need, the next step depends on the drug's protection:
    • If it still has an unexpired listed patent or extendable exclusivity, FDA decides whether to require an assessment under PREA section 505B(b).
    • If it has neither, FDA refers it to the list under 42 U.S.C. 284m for publicly funded studies.
  • Biologics: subsection (n) refers to extendable exclusivity under PHS Act section 351(m)(2) and (m)(3) (42 U.S.C. 262(m)). The biologics provision itself is outside section 355a and I did not review it here.

Where BPCA mirrors PREA

  • Pediatric labeling applications under BPCA "shall be considered" priority applications (subsection (i)(1)).
  • Labeling disputes follow the same steps as PREA: referral to the Pediatric Advisory Committee, then possible misbranding (subsection (i)(2)).
  • FDA "shall order" the labeling to show the study results, including inconclusive ones (subsection (j)).
  • FDA publishes its reviews within 210 days (subsection (k)).
  • For 18 months after a labeling change, adverse event reports go to the Office of Pediatric Therapeutics (subsection (l)).
  • Generics (subsection (o)): a 505(b)(2) or ANDA product may leave out a pediatric indication protected by patent or exclusivity. That omission does not make it unapprovable or misbranded. FDA may require a statement that it is not labeled for that pediatric use, plus any warnings needed for safe use.

Sunset: Pub. L. 112-144 (July 9, 2012) removed the former subsection (q), which limited the six months to drugs whose Written Request and filing came on or before October 1, 2012. The section as printed has no expiry date.

Q.03

Which pediatric age groups does the FDA use?

FDA uses the same four pediatric subgroups everywhere (neonates, infants, children, adolescents), but the upper age limit depends on the product. For drug and biologic labeling, "pediatric" means birth to 16 years. For medical devices, it means 21 years or younger. Neither PREA nor BPCA sets numeric age bands for drugs.

Approach: I read the FD&C Act (2023 U.S. Code, 21 U.S.C. 355a, 355c, 360e-1 and 360j), FDA's CDRH pediatric guidance documents, and the current eCFR text of 21 CFR 201.57. I did not review ICH E11 or any CDER pediatric guidance for drug age bands.

Drugs and biologics

  • PREA (505B): the statute talks about "each age group", "all relevant pediatric subpopulations" and "a specific pediatric age group" (for partial waivers) but never defines them [1].
  • BPCA (505A): "pediatric studies" means at least one clinical investigation "in pediatric age groups (including neonates in appropriate cases) in which a drug is anticipated to be used" [4].
  • Labeling, 21 CFR 201.57(c)(9)(iv)(A) (section 8.4 Pediatric Use): "pediatric population(s)" and "pediatric patient(s)" are "defined as the pediatric age group, from birth to 16 years, including age groups often called neonates, infants, children, and adolescents." The rule gives no age limits for each subgroup. Labeling must state the age ranges where safety and effectiveness are established ("in the age groups ___ to _"). Where they are not, it must say "Safety and effectiveness in pediatric patients below the age of () have not been established." (eCFR 21 CFR 201.57)

Medical devices

  • Statute, section 520(m)(6)(E): "pediatric patients" means patients "21 years of age or younger at the time of the diagnosis or treatment." "Pediatric subpopulation" means neonates, infants, children or adolescents [6]. Section 515A(c) (21 U.S.C. 360e-1) uses the same definition [5].
  • Regulation: 21 CFR 814.3(s) defines pediatric patients the same way: from birth up to, but not including, the 22nd birthday. The age range for each subgroup is set in guidance, not in the rule [7].

The guidance age ranges are:

SubgroupCurrent CDRH ranges ("Providing Information about Pediatric Uses of Medical Devices", 2014; 2016 extrapolation guidance; 2026 human factors guidance)Older 2014 "Premarket Assessment of Pediatric Medical Devices"
NeonateBirth through the first 28 daysBirth to 1 month
Infant29 days to under 2 yearsOver 1 month to 2 years
Child2 years to under 12 yearsOver 2 to 12 years
Adolescent12 through 21 years (up to, not including, the 22nd birthday)Over 12 through 21 years

Sources for the table: [7][8][9][10][11]

Points that affect device submissions:

  • Why days instead of months: the newer guidance sets the neonate/infant boundary in days to match national statistical standards for neonatal and infant mortality [8].
  • Ages 18 to 21: for PMA and HDE review, FDA considers whether "older adolescents" (18 through 21) need special consideration. Sponsors "should include" any such considerations if the information is readily available [8].
  • Other biological factors: the age bands may not decide whether extrapolation works. Skeletal maturity, for example, can matter more in orthopedic disease [9].
  • Product-specific variation: the January 2025 draft guidance on pulse oximeters uses slightly different bands for labeling: neonates birth to 30 days, infants 1 month to under 2 years, children 2 to under 12 years [12].

What this means in practice

For drug and biologic labeling, the definition stops at 16 years. For devices, it runs through age 21, so 17- to 21-year-olds count as pediatric for a device PMA or HDE. When a drug-device combination or a companion device is involved, set out which definition applies to each part.

Q.04