Research · 6 min read
What Requires a Drug to Be Studied in Children
A federal statute makes pediatric assessments a condition of certain applications, then supplies two ways out — a deferral and a waiver — each with its own written grounds. A third mechanism reaches drugs already on the market.
Key takeaways
- Pediatric assessments are required with applications for a new active ingredient, indication, dosage form, dosing regimen or route of administration — four of which apply to already-approved drugs.
- The assessments must support both safety and effectiveness in relevant pediatric subpopulations and dosing for each subpopulation in which the product is safe and effective.
- Extrapolation from adult studies is permitted where disease course and drug effects are sufficiently similar, and the supporting reasoning must be documented in the application's reviews.
- A deferral postpones the assessments but requires a certification, a study plan, evidence of due diligence and a timeline, with 90-day advance notice to request an extension.
- Waivers have enumerated grounds, including that a product is not likely to be used in a substantial number of pediatric patients and offers no meaningful benefit over existing pediatric therapies.
- Non-compliance letters and the companies' written responses are published on FDA's website 60 days after issuance, and unresolved pediatric labeling disputes can end in a misbranding determination.
Answer first: five triggers, and the requirement attaches to the application
The rule is in 21 U.S.C. 355c. A person who submits an application, or a supplement to one, for a drug "for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration" must submit with it the assessments the section describes. The same requirement applies to applications for biological products under the Public Health Service Act.
Those five triggers are worth reading closely, because four of them apply to drugs that already exist. A new indication, a new dosage form, a new dosing regimen or a new route of administration each starts the obligation afresh. The requirement is attached to what is being asked for, not only to a molecule's first appearance.
What has to be submitted is defined by function. The assessments must contain data, "gathered using appropriate formulations for each age group for which the assessment is required," adequate "to assess the safety and effectiveness of the drug or the biological product for the claimed indications in all relevant pediatric subpopulations" and "to support dosing and administration for each pediatric subpopulation for which the drug or the biological product is safe and effective."
That last clause is a conditional. Dosing information is required for each subpopulation in which the product is safe and effective — which presupposes that some subpopulations may not be.
Extrapolation, and the documentation it requires
The statute does not require every question to be answered from scratch in every age group. It permits extrapolation, and states the conditions.
"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 adults, usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies." A second clause allows the same reasoning between age groups: "A study may not be needed in each pediatric age group if data from one age group can be extrapolated to another age group."
There is a paper trail requirement attached. "A brief documentation of the scientific data supporting the conclusion... shall be included in any pertinent reviews for the application." So an extrapolation is a documented conclusion in the review record rather than an unspoken assumption, which is the difference between a decision a reader can go and look up and one they cannot.
The two ways out, and what each one costs
The first is a deferral, which postpones rather than removes. FDA may defer submission of some or all assessments "until a specified date after approval of the drug" if it finds that the product "is ready for approval for use in adults before pediatric studies are complete," that pediatric studies "should be delayed until additional safety or effectiveness data have been collected," or that "there is another appropriate reason for deferral."
The applicant must supply four things: a certification of the grounds, a pediatric study plan, "evidence that the studies are being conducted or will be conducted with due diligence and at the earliest possible time," and a timeline for completion. Extensions are available on a further showing, and where the applicant requests one it must be filed not less than 90 days before the deferral would expire, with FDA responding within 45 days.
The second is a waiver, and the grounds are enumerated. A full waiver shall be granted where "necessary studies are impossible or highly impracticable (because, for example, the number of patients is so small or the patients are geographically dispersed)"; where "there is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in all pediatric age groups"; or where the product "does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients" and "is not likely to be used in a substantial number of pediatric patients." Note that the third ground is conjunctive: both halves must hold.
A partial waiver covers a specific age group on the same grounds applied to that group, plus one more — that "the applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed." Where a partial waiver is granted because a pediatric formulation is not possible, the applicant's supporting documentation "shall promptly be made available to the public in an easily accessible manner, including through posting on the Web site of the Food and Drug Administration."
The plan comes first, and noncompliance is published
Before the assessments, there is a plan. An applicant subject to the requirement must submit an initial pediatric study plan before submitting the assessments, and not later than 60 calendar days after the end-of-Phase 2 meeting, or such other time as agreed with FDA.
The plan's contents are specified: an outline of the studies the applicant plans to conduct, including to the extent practicable the objectives and design, age groups, relevant endpoints and statistical approach, together with any request for a deferral or waiver.
Failure carries a published consequence. Where a person fails to submit a required assessment, fails to meet the deferral requirements, or fails to submit a request for approval of a pediatric formulation, FDA "shall issue a non-compliance letter to such person informing them of such failure," and the letter requires a written response within 45 calendar days. Then the part that matters for anyone trying to check: "Such letter and the person's written response to such letter shall be made publicly available on the Internet Web site of the Food and Drug Administration 60 calendar days after issuance, with redactions for any trade secrets and confidential commercial information."
The statute also states the legal effect: the product "may be considered misbranded solely because of that failure and subject to relevant enforcement action." And FDA must inform the Pediatric Advisory Committee of the letters and the responses.
Marketed drugs, and how a pediatric result reaches the label
The requirement is not limited to new applications. FDA may, by order in the form of a letter, require the holder of an approved application to submit pediatric assessments by a specified date where it finds that the product "is used for a substantial number of pediatric patients for the labeled indications" and "adequate pediatric labeling could confer a benefit on pediatric patients"; or that there is reason to believe the product "would represent a meaningful therapeutic benefit over existing therapies for pediatric patients" for one or more claimed indications; or that "the absence of adequate pediatric labeling could pose a risk to pediatric patients."
Waivers are available against that order too, on grounds that track the ones above.
Getting the result onto the label has its own machinery, and it ends somewhere unusual. If the Commissioner determines that a sponsor and the Commissioner cannot agree on appropriate labeling changes, the Commissioner requests the change; if the sponsor does not agree within 30 days, the matter is referred to the Pediatric Advisory Committee, which has 90 days to review the pediatric study reports and recommend labeling changes. The Commissioner then considers the recommendation and, if appropriate, makes a further request.
And if the sponsor still does not agree within 30 days of that request, "the Commissioner may deem the drug that is the subject of the application or supplement to be misbranded." The statute adds that nothing in the subsection limits the authority to bring an enforcement action where a drug lacks appropriate pediatric labeling, and that neither route precludes or delays the other.
What a reader can check, and what a pediatric label means
Three things in this section are publicly verifiable by design, which makes them the useful ones. Noncompliance letters and the responses to them are published on FDA's website 60 days after issuance, with redactions. Documentation supporting a partial waiver granted because a pediatric formulation could not be developed is to be made publicly available. And an extrapolation conclusion is required to be documented in the pertinent reviews for an application.
Two cautions follow from the structure. A drug without pediatric labeling has not necessarily been found unsafe in children — the statute supplies deferrals and waivers, including a waiver where a product is not likely to be used in a substantial number of pediatric patients. Equally, a deferral is not an exemption: it comes with a certified timeline, evidence of due diligence, and an expiry.
This article makes no claim about any specific product. Whether a particular drug carried a pediatric requirement, received a deferral or a waiver, or has pediatric labeling is a fact about that application, and it belongs in the documents FDA publishes about it rather than in a general description of the statute.
Sources
- 21 U.S.C. 355c — Research into pediatric uses for drugs and biological products (subsections (a), (b), (d), (e) and (g))The five triggering circumstances for a required pediatric assessment; the content requirements for assessments including appropriate formulations, relevant pediatric subpopulations and dosing support; the extrapolation provisions between adults and children and between age groups, and the requirement to document the supporting scientific data in pertinent reviews; the deferral grounds and the four items an applicant must submit, plus the 90-day and 45-day extension timing; the full and partial waiver grounds, including the conjunctive benefit-and-use ground and the failed-formulation ground, and the public availability of documentation supporting a formulation-based partial waiver; the initial pediatric study plan and its timing and contents; the non-compliance letter, the 45-day response, the 60-day publication with redactions, the misbranding consequence and notice to the Pediatric Advisory Committee; the order-by-letter authority for marketed products and its three findings; and the labeling dispute resolution process ending in a possible misbranding determination.
Frequently asked questions
What triggers a pediatric assessment requirement?
An application or supplement for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration. Four of those five triggers can apply to a drug that is already approved, because the obligation attaches to what the application asks for.
What do the assessments have to contain?
Data gathered using appropriate formulations for each age group for which the assessment is required, adequate to assess safety and effectiveness for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each subpopulation in which the product is safe and effective.
Can data from adults be used instead?
The statute permits it under conditions. Where the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, effectiveness may be extrapolated from adequate and well-controlled adult studies, usually supplemented with other pediatric information such as pharmacokinetic studies, and a study may not be needed in every age group if data can be extrapolated between groups. Brief documentation of the supporting scientific data must appear in the pertinent reviews.
When is a pediatric study waived?
A full waiver shall be granted where necessary studies are impossible or highly impracticable, where evidence strongly suggests the product would be ineffective or unsafe in all pediatric age groups, or where the product both does not represent a meaningful therapeutic benefit over existing pediatric therapies and is not likely to be used in a substantial number of pediatric patients. Partial waivers apply the same grounds to a specific age group and add failure of reasonable attempts to produce a necessary pediatric formulation.
What happens if a company does not comply?
FDA issues a non-compliance letter requiring a written response within 45 calendar days, and both the letter and the response are made publicly available on FDA's website 60 calendar days after issuance, with redactions for trade secrets and confidential commercial information. The statute also provides that the product may be considered misbranded solely because of the failure.
Can FDA require pediatric studies of a drug already on the market?
Yes. It may require assessments by order in the form of a letter where it finds the product is used for a substantial number of pediatric patients for its labeled indications and adequate pediatric labeling could confer a benefit, or that the product would represent a meaningful therapeutic benefit for pediatric patients, or that the absence of adequate pediatric labeling could pose a risk.