21 U.S.C. § 355c — Research into pediatric uses for drugs and biological products

(a) New drugs and biological products. (1) In general. Starting September 27, 2007, if someone applies for a drug approval under section 355 (or a biologic under section 262 of title 42) for a new active ingredient, new use, new dosage form, new dosing schedule, or new route of giving the drug, they must submit the pediatric assessments described in paragraph (2) — unless the molecularly targeted cancer rule below applies instead. Starting three years after August 18, 2017, if someone submits an original application for a new active ingredient to treat adult cancer, and the drug targets a molecular target the Secretary decides is closely tied to a pediatric cancer's growth, they must instead submit the investigation reports described in paragraph (3). An application cannot be subject to both requirements — only one applies. (2) Assessments. These assessments must include data, gathered with the right formulation for each age group, good enough to judge the drug's safety and effectiveness for children, and to support proper dosing for each pediatric group where it is safe and effective. If the disease and the drug's effects are similar enough in adults and children, the Secretary may allow the effectiveness data from adult studies to apply to children too, usually backed up with other pediatric information like pharmacokinetic studies. A study might not be needed for every age group if data from one age group can carry over to another, but any such conclusion needs a brief written explanation in the application review. (3) Molecularly targeted pediatric cancer investigation. For purposes of paragraph (1)'s cancer rule, this is an investigation of the drug itself, or the drug combined with: an already-approved drug or biologic that the Secretary, after talking with the applicant, decides is part of the standard pediatric cancer treatment; or another drug or biologic approved to treat adult cancer, held by the same applicant, and targeting a molecular target tied to pediatric cancer. The investigation must be designed to produce clinically useful pediatric data — on dosing, safety, and early effectiveness — using the right formulation for each age group. This kind of investigation can only be required if the drug has a single new active ingredient, or has more than one active ingredient where the combination has not been approved before but each ingredient individually has been approved to treat adult cancer. The Secretary may require completed preclinical study results to be submitted along with the initial pediatric study plan. This provision does not address how inactive ingredients in a combination are handled. The same data-extrapolation rules described above apply here too, and the deferral and waiver rules in paragraphs (4) and (5) apply to these investigations the same way they apply to paragraph (1) assessments. (4) Deferral. The Secretary, on their own initiative or at the applicant's request, can delay submission of some or all assessments or investigation reports until after the drug or biologic is approved, if: the drug is ready for adult approval before pediatric studies finish; pediatric studies should wait for more safety or effectiveness data; or there is some other good reason. The applicant must certify the reasons for deferral, submit a pediatric study plan, show the studies are or will be done diligently and as early as possible, and give a completion timeline. The Secretary, on their own initiative or at the applicant's request, can extend an approved deferral if the same conditions still apply and the applicant provides an updated timeline and any significant updates. If the applicant requests the extension, they must ask at least 90 days before the deferral expires, and the Secretary must respond within 45 days; a granted extension moves the deadline to the new date. The Secretary will not issue a noncompliance letter (described in subsection (d)) unless the deadline has passed or an extension request is still pending. Every year after a deferral is approved, the applicant must report: progress on the studies; if there is no progress, evidence the studies will still be done diligently and promptly; a projected completion date; and why the deferral is still needed. Within 90 days of getting that report, the Secretary must make it public — including on the FDA website — along with the applicant's name, the drug's approval date, and the dates of each deferral or extension. (5) Waivers. The Secretary must grant a full waiver of the assessment or investigation requirement if the applicant shows: the necessary studies are impossible or highly impractical (for example, too few patients, or patients too spread out); there is strong evidence the drug would be unsafe or ineffective in all pediatric age groups; or the drug does not offer a meaningful benefit over existing pediatric therapies and is not likely to be used by many children. The Secretary must grant a partial waiver for a specific age group on similar grounds: impossible or impractical studies for that group; strong evidence of unsafe or ineffective use in that group; no meaningful benefit and low likely use in that group; or a demonstrated failure, despite reasonable attempts, to create a pediatric formulation for that group. If the waiver is granted because a formulation cannot be made, it only covers the age groups needing that formulation, and the applicant's explanation for why it cannot be developed must be made public once the waiver is granted. If a waiver is granted because the drug would be unsafe or ineffective for children, the label must say so. (b) Marketed drugs and biological products. The Secretary can order, by letter, the holder of an approved drug or biologic to submit the same kind of pediatric assessments by a set date, if: the drug is already used by many pediatric patients and better pediatric labeling would help them; there is reason to think the drug offers a meaningful benefit over existing pediatric therapies; or missing pediatric labeling could be risky for children. The same full-waiver and partial-waiver rules described in subsection (a) apply here at the applicant's request, on the same grounds, including no meaningful benefit and no significant safety risk from missing labeling, or a documented failure to create a needed formulation, and the same public-disclosure and labeling rules apply too. None of this changes section 331(j) of this title, section 552 of title 5, or section 1905 of title 18. (c) Meaningful therapeutic benefit. For purposes of the waiver standards above, a drug counts as offering a meaningful therapeutic benefit if the Secretary decides that, if approved, it would improve treatment, diagnosis, or prevention compared to existing pediatric-labeled products, or if it fills a need in a product class or for a use where more options are needed. (d) Submission of assessments and reports on the investigation. If someone fails to submit a required assessment, investigation, deferral requirement, or pediatric formulation request on time, the following applies. Starting 270 days after July 9, 2012, the Secretary must send a noncompliance letter, giving the person 45 days to respond in writing (possibly including a deferral extension request). The letter and response become public after 60 days, with trade secrets redacted — unless the Secretary decides the letter was sent in error, in which case none of this applies. The Secretary must tell the Pediatric Advisory Committee about these letters and responses. The drug can be treated as misbranded solely for that failure, and can face enforcement action — but only under section 333 if the person clearly was not diligent. This failure alone cannot be used to withdraw drug approval under section 355(e) or revoke a biologic license under section 262. The Secretary cannot bring a section 333 enforcement action over this kind of failure for a drug that is no longer on the market. Before deciding someone failed to meet a requirement, the Secretary must send the noncompliance letter, give the person 45 days to respond, and review that response before deciding whether the person lacked diligence. (e) Pediatric study plans. Before submitting the pediatric assessments or investigation, an applicant under subsection (a) must submit an initial pediatric study plan. The Secretary must decide, before that plan is due, whether the general rule or the cancer rule in subsection (a) applies. The plan is due before the assessments are submitted, and no later than 60 days after the end-of-Phase-2 meeting (or another time agreed with the Secretary); it can be submitted earlier. The plan must outline the planned studies (objectives, design, age groups, endpoints, statistics), include any deferral or waiver request with support, and cover anything else required by regulation. The Secretary must meet with the applicant — on request, for a serious or life-threatening disease, by the end-of-Phase-1 meeting or within 30 days of the request; to discuss the study plan within 90 days of getting it; and to discuss deferral or waiver requests — though the Secretary can instead respond in writing within that same 90 days if a meeting is not needed. Within 90 days of that meeting or written response, the applicant must submit a document titled "Agreed Initial Pediatric Study Plan," and the Secretary must confirm agreement in writing within 30 days. If the agreed plan includes a deferral or waiver request, the Secretary's written confirmation must say whether it meets the applicable standards. The plan can be amended anytime, by either side, following the same meeting and agreement process as the original plan. The Secretary must consult the internal committee (under section 355d) when reviewing the plan and any major amendments. Within one year of July 9, 2012, the Secretary had to propose regulations and issue guidance to implement this subsection. (f) Review of pediatric study plans, assessments, deferrals, deferral extensions, and waivers. Starting no later than 30 days after September 27, 2007, the Secretary must use the internal committee to advise reviewing divisions on study plans, agreed plans, amendments, and assessments before approving an application, and on all deferral, extension, and waiver requests; the committee can act with just some members present, but must record for each drug which members participated in each review. This consultation happens before approval, and the committee reviews every deferral, extension, and waiver request and gives recommendations to reviewing divisions, including on whether a supplement should get priority review. Within one year of September 27, 2007, the committee had to review a representative sample of assessments, deferrals, and waivers approved since December 3, 2003, judging their quality and consistency, and the Secretary had to issue improvement recommendations and guidance based on that review. The Secretary, with the committee, must track and publish — including on the FDA website — things like: how many assessments were done; which drugs and uses were studied; study types and details; yearly totals of deferrals and extensions requested and granted (with reasons), assessment timelines, completed and pending assessments, and noncompliance letters issued; how many waivers were requested and granted (with reasons); how many pediatric formulations were and were not developed and why; resulting labeling changes; annual summaries of those changes and of deferral-related information; and how often the committee recommended priority review, and whether the Secretary followed that recommendation. (g) Labeling changes. If the Commissioner and a sponsor cannot agree on labeling changes within 180 days (priority review) or 330 days (standard review) of the application or supplement, the Commissioner asks the sponsor to make the change; if the sponsor refuses within 30 days, the Commissioner refers the matter to the Pediatric Advisory Committee, which must review the study reports and recommend labeling changes within 90 days. The Commissioner considers the recommendation and, if appropriate, asks the sponsor again within 30 days; if the sponsor still refuses within 30 days, the Commissioner can treat the drug as misbranded. None of this limits separate enforcement action for missing pediatric labeling, and neither process blocks the other. Separately, if the Secretary decides a pediatric assessment does, does not, or inconclusively shows the drug is safe and effective for children, the Secretary must order the label to describe the results and the Secretary's conclusion. (h) Dissemination of pediatric information. Within 210 days (priority review) or 330 days (standard review) of an application containing a pediatric assessment, the Secretary must make the medical, statistical, and clinical pharmacology reviews public and post them on the FDA website. The Secretary must require sponsors whose assessments led to labeling changes reflected in the annual summary to distribute that information to health care providers. None of this changes section 331(j), section 552 of title 5, or section 1905 of title 18. (i) Adverse event reporting. For the 18 months after a labeling change under subsection (g), the Secretary must send every adverse event report about the drug to the Office of Pediatric Therapeutics, whose Director must have the Pediatric Advisory Committee review them and recommend whether the Secretary should act. After that 18 months, the Secretary must still refer pediatric adverse event reports to the Office as appropriate, and the Director may still send them to the Committee. The Office can still send reports to the Committee even before the 18 months starts, if needed for safety. These requirements add to, not replace, the Secretary's other adverse-event review. (j) Scope of authority. This section does not give the Secretary any power to require pediatric assessments, or assessments of other populations or uses, beyond what this section specifically describes. (k) Relation to orphan drugs. Unless the Secretary says otherwise by regulation, this section does not apply to a drug for a use that has orphan-drug designation under section 360bb — except that this section does apply to an orphan-designated drug if the molecularly targeted pediatric cancer investigation in subsection (a) applies to it under the cancer rule. (l) New active ingredient. A biosimilar biologic that the Secretary has not found interchangeable with its reference product counts as having a "new active ingredient" under this section. A biosimilar biologic that is interchangeable with its reference product does not count as having a new active ingredient. (m) List of primary molecular targets. Within one year of August 18, 2017, the Secretary had to create, regularly update, and publish on the FDA website: a list of molecular targets considered closely tied to pediatric cancer growth, which can trigger this section's requirements; and a list of molecular targets for new cancer drugs in development that are automatically waived from pediatric cancer study requirements. The Secretary must consult the National Cancer Institute, members of the internal committee under section 355d, and the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee, and must consider comments from the meeting referenced in subsection (c). Nothing in this listing requirement means a molecular target must be on the published list before the pediatric cancer requirements can apply to a drug targeting it, and nothing here allows the Secretary to disclose confidential business information otherwise protected under section 331(j) or section 1905 of title 18.