21 U.S.C. § 355h — Regulation of certain nonprescription drugs that are marketed without an approved drug application

(a) Nonprescription drugs marketed without an approved application. This subsection covers over-the-counter (OTC) drugs that, as of March 27, 2020, were being sold without an FDA-approved drug application. (1) Drugs subject to a final monograph, or Category I drugs subject to a tentative final monograph. A drug counts as "generally recognized as safe and effective" (GRASE) — meaning it's not a "new drug" needing approval, and not limited to prescription-only sale — if either: (A) it follows a final monograph's rules for OTC use (except for sunscreens, covered in paragraph (2)), plus general OTC drug rules and any conditions set under subsections (b), (c), and (k), and it's sold in a dosage form that was already commonly used before March 27, 2020, unless a different form was allowed by a (b) order or a minor-change (c) order; or (B) it's classified "Category I" (safe and effective) under the most recent tentative final monograph proposal, it follows that proposal's requirements plus any later FDA decision, general OTC rules, and (b)/(c)/(k) conditions, and it's likewise in a dosage form already commonly used before March 27, 2020, subject to the same exceptions. (2) Treatment of sunscreen drugs. For sunscreens, the "final monograph" in paragraph (1)(A)(i) means the specific sunscreen regulation published May 21, 1999 (21 CFR part 352), except that the rules for how well the sunscreen must work and what its label must say come from a different regulation, 21 CFR 201.327. (3) Category III drugs subject to a tentative final monograph; Category I drugs subject to a proposed monograph or advance notice. A drug not covered by (1), (2), or (4) doesn't need an approved application and isn't limited to prescription-only sale if either: (A) it's classified "Category III" (needs more data) in the most recent tentative final monograph proposal, it matches the described conditions of use and dosage, follows the Category I requirements from the most recent proposed and any final rule, follows general OTC rules and (b)/(k) conditions, and its dosage form was already commonly used before March 27, 2020; or (B) it's classified Category I under a proposed monograph or an early-stage "advance notice of proposed rulemaking" that's the most recent one for that drug, it follows that proposal's requirements plus any later FDA decision and general OTC rules and (b)/(k) conditions, and its dosage form was already commonly used before March 27, 2020. (4) Category II drugs deemed new drugs. A drug classified "Category II" (not safe or effective) in the most recent proposed rule becomes a "new drug" — misbranded and needing an approved application — 180 days after March 27, 2020, unless before then the FDA decides it's better for public health to let it keep being sold without approval for longer. (5) Drugs found not GRASE deemed new drugs. If the FDA has made a final determination that a drug isn't generally recognized as safe and effective, that drug automatically becomes a "new drug," is misbranded, and needs an approved application. (6) Other drugs deemed new drugs. Unless subsection (m) says otherwise, a drug is a "new drug" and misbranded if it (A) isn't limited to prescription-only sale, and (B) doesn't fit into paragraphs (1) through (5) above or subsection (b)(1)(B). (b) Administrative orders. This is the core process FDA now uses, instead of old-style monograph rulemaking, to decide which OTC drugs can be sold without a full drug approval. (1) In general. (A) The FDA — on its own initiative or at a "requestor's" request — can issue an "administrative order" deciding whether a specific drug, class of drugs, or combination is (i) not limited to prescription-only sale, and (ii) generally recognized as safe and effective. (B) A drug covered by such an order doesn't need approval if it meets both conditions in (A), is sold following the order, meets general OTC drug rules, and meets the requirements in subsections (c) and (k). (C) The FDA must find a drug is NOT generally recognized as safe and effective if either the evidence shows it isn't, or the evidence just isn't good enough to show that it is. (2) Orders initiated by the FDA. (A) When FDA starts this process itself, it must: try to informally notify listed drug sponsors at least 2 business days before proposing the order; then publish the proposed order (with its reasons) on FDA's website and publish notice of it in the Federal Register; allow at least 45 days of public comment (except as (B) below changes this); and, if FDA then decides to finalize the order, issue the final order with detailed reasons (which doesn't take effect until the deadline to seek court review passes), publish notice in the Federal Register, let sponsors formally dispute the decision up through the Director of the Center for Drug Evaluation and Research (first request within 45 days, later appeals within 30 days), and then — except for drugs described in paragraph (3)(B) — tell the parties they can request a hearing. (B) For drugs that might be found not GRASE under subsection (a)(3), FDA follows the same steps but must also: tell people in the proposed order what data would be needed to prove the drug safe and effective and how to submit it; give at least 180 days for comment, unless a shorter period is needed for public health reasons; and require anyone submitting data to certify they've turned in everything relevant they have. (3) Hearings and judicial review. (A) Only someone who went through every stage of formal dispute resolution on an order can request a hearing about it, and must do so within 30 days of the final dispute-resolution decision, based only on the existing record. (B) No hearing is required if the order deals with a drug classified Category III under (a)(3)(A) and no new human or non-human safety data has been added to the record since the last tentative final monograph. "Human data studies" means clinical trials (including real-world "actual use" studies), pharmacokinetic studies, or bioavailability studies; "non-human data" means non-human test data bearing on safety or effectiveness. (C) Hearing procedures: FDA can deny a hearing request that doesn't raise a genuine, substantial factual dispute based on scientifically reliable evidence; multiple requests about the same order can be combined into one hearing; the hearing officer must be picked by the FDA, can't work for the Center for Drug Evaluation and Research, and can't have helped develop that order; parties can present testimony (including experts) and cross-examine other parties' witnesses, and the officer can require parties with similar interests to combine their cross-examination; and after the hearing, the officer issues a final decision with findings of fact and legal conclusions, which doesn't take effect until the judicial-review deadline passes. (D) Judicial review follows the same court procedures used for drug-approval order review under section 355(h), except the case goes to a federal district court instead of an appeals court; a person must file for review within 60 days of the latest of: when notice of the order was published, when a hearing was denied, when a final hearing decision came out, or (if no hearing was requested) when the deadline to request one passed. (4) Expedited procedure for FDA-initiated orders. (A) If FDA decides a drug poses an imminent public-health hazard, it can — after trying to notify sponsors at least 48 hours ahead — issue an interim final order right away with detailed reasons, publish notice in the Federal Register, and allow at least 45 days of comment; this power can't be delegated away from the Secretary. (B) If FDA decides a labeling change is reasonably likely to reduce a serious safety risk, it can, after similar 48-hour notice efforts, issue an interim final order requiring the change (which can add new warnings or safety information), with reasons, Federal Register notice, and at least 45 days of comment. (C) These interim orders take effect on a date FDA sets. (D) Afterward FDA must issue a final order, publish notice, and give sponsors a chance for formal dispute resolution (first request within 45 days, later appeals within 30 days). (E) A sponsor who went through all dispute-resolution stages can request a hearing, using the same rules as paragraph (3)(A)-(C) except for the timing of when a final hearing decision takes effect. (F) FDA must issue a final order within 6 months after the comment period closes, and finish any hearing within 12 months after that; the interim order must set shorter dispute-resolution deadlines as needed to meet these timelines. (G) A final order here can be challenged in court the same way as under paragraph (3)(D). (5) Orders requested by a requestor. (A) When a "requestor" asks for an order: FDA first checks whether the request is complete and properly formatted; if so, FDA files it and starts the paragraph (2)/(3) process; if not (and paragraph (6) doesn't apply), the requestor can insist ("file over protest") and FDA must still review it under paragraph (2)(A). (B) A requestor submits a request in FDA's required format, either to get a drug declared GRASE, non-prescription-only, and exempt from needing approval, or to get a *change* in how a drug is used declared likewise fine — but only if, without that change, the drug already qualifies under (a)(1), (a)(2), an existing order, or (linked to a request about the base drug) subsection (a)(3). FDA doesn't have to finish reviewing a change request if it decides there's not enough evidence the drug is GRASE and issues a final order saying so. The requestor can withdraw the request under FDA's procedures, and FDA can then stop working on it. (C) Exclusivity: a final order granted at a requestor's request gives only that requestor (or their licensees/successors) the sole right, for 18 months starting when they can lawfully begin selling under the order, to market drugs with qualifying changes — either adding a new active ingredient (or its ester/salt) not used before in a covered drug, or changing how the drug is used where new human studies paid for or controlled by the requestor were essential to getting the order. "Covered" drugs are those under (a)(1)/(2)/(3), subject to a final order, subject to a final sunscreen order, or described in subsection (m)(1) (other than ones facing active enforcement). Only one 18-month exclusivity period is given per order per drug, covering either the active-ingredient change or the conditions-of-use change, not both separately; no exclusivity applies to changes that are the subject of a "Tier 2" monograph request, safety-related changes FDA requires, or changes to testing methods. "New human data studies" means clinical, pharmacokinetic, or bioavailability studies whose results weren't already relied on by FDA for a GRASE finding or drug approval, and don't just repeat another study FDA already relied on for that purpose. A requestor with exclusivity must tell FDA in writing, within 1 year of the final order, if the drug won't be for sale within a year — including its name, strength, expected sale date if known, and why it isn't being marketed. (6) Safety information as a condition for filing a GRASE request. (A) When someone requests that a drug described in (B) be found GRASE, FDA can file the request only if it includes the safety information described in (C); otherwise FDA must refuse to file it and require the drug to go through the new-drug-application process in (D). (B) This applies to a nonprescription drug with an active ingredient never before used in a drug covered by (a)(1)/(2)/(3), a final order, or a final sunscreen order. (C) The required information is proof the drug has a track record of safe OTC use in the U.S. under similar conditions; or, if it's never been sold OTC in the U.S., proof of safe marketing and use under similar conditions in another qualifying country for long enough to be reassuring and under sufficient regulatory monitoring including for adverse events; or, if FDA decides that isn't needed, whatever other information FDA says is enough. (D) If a request is refused, the drug can only be resubmitted after it's sold as a nonprescription drug, under comparable conditions, for up to 5 years, under a section 355-approved application, and during that time 1,000,000 retail packages (or an FDA-set equivalent amount) were sold at retail. (E) Except for a specific drug described in section 360fff(9) as it existed on January 1, 2017, if FDA refuses to file a request here, the requestor can't force the issue by filing "over protest." (7) Packaging. Orders under paragraph (2), (4)(A), or (5) can require special packaging — like single-dose packets, child-focused packaging, or measures against accidental swallowing — to encourage safe, correct use. This doesn't let FDA impose the child-resistant packaging standards found in a separate consumer-safety regulation (16 CFR part 1700). (8) Final and tentative final monographs deemed final orders. (A) A final or tentative final monograph described in (B) counts as a final administrative order under this subsection and can be amended, revoked, or changed using this subsection's procedures. (B) This applies to a monograph that sets conditions of use for a drug under (a)(1) or (2) and represents the newest version of those conditions, including partial updates from later rules. (C) These "deemed" orders automatically include any technical fixes FDA decides are needed to keep terms and cross-references consistent with the rest of the law and other orders under this section. (c) Procedure for minor changes. (1) A requestor can make a minor change to the dosage form of a drug covered by (a)(1)/(2) or an existing (b) order, without a new order, if the requestor keeps records showing the change won't affect safety or effectiveness and won't materially change how much of the active ingredient the body absorbs compared to a reference product, and the change follows any applicable FDA order under paragraph (3). (2) A sponsor must turn over requested records about such a change within 15 business days (or longer if FDA allows). If FDA decides the records don't prove the change is safe or doesn't affect absorption, it can tell the sponsor in writing and must give a fair chance to submit more information; if the sponsor doesn't do so in time, or the added information still doesn't prove the change is safe, the changed drug becomes a "new drug" and is misbranded. (3) FDA must issue orders spelling out how to judge whether a minor change affects safety, effectiveness, or absorption, plus guidance for specific dosage forms, taking into account relevant public quality standards and the special needs of populations like children. (d) Confidentiality. (1) Information (including test reports) a requestor submits in a section 355h proceeding — including minor-change proceedings — that qualifies as a trade secret or confidential business information under federal law can't be publicly disclosed unless the requestor agrees. (2) Except as limited below, FDA must make public: information a requestor submits to support a request under (b)(5)(A), by the time the proposed order issues; and information anyone else submits about an order (requested or FDA-initiated) under (b), as soon as it's submitted. But information stays private if it's pharmaceutical quality information (unless needed to set GRASE standards); it was submitted for a requestor-initiated request the requestor withdrew before the proposed order issued; FDA obtained it under subsection (c) and it wasn't tied to a (b) order; or it's raw dataset-type information. (e) Updates to drug listing information. A sponsor who changes a covered drug must update its listing information within 30 days of first marketing the changed drug — except a sponsor who was the requestor behind an order carrying (b)(5)(C) exclusivity (or their licensee/successor) must update the listing by the date the drug is first marketed. (f) Approvals under section 355. This section doesn't stop anyone from also seeking or keeping a full drug-application approval. A determination under this section that a drug isn't prescription-only, is GRASE, and isn't a "new drug" counts as an official safety-and-effectiveness finding that can support certain other kinds of drug applications, meaning the applicant only has to submit information about whatever part of the drug isn't already covered by that determination. (g) Public availability of orders. FDA must maintain and publicly post, updating at least once a year, a full-text repository of every final and interim final order in effect, and a list of every order proposed or in development, with a brief description of each and (resources permitting) FDA's expected timeline for proposing orders over the next 3 years. (h) Development advice. FDA must set up procedures letting sponsors, requestors, or groups representing them meet with FDA officials for advice on what studies and information they need. (i) Multiple sponsors or requestors. FDA must create procedures to let multiple sponsors or requestors — or groups representing them — participate efficiently in a proceeding, including joint meetings. (j) Electronic format. Everything submitted under this section must be submitted electronically. (k) Effect on existing regulations. (1) Except as this subsection says otherwise, this section doesn't override general OTC drug regulations; FDA can only change those rules through normal notice-and-comment rulemaking. (2) The regulation at 21 CFR 310.545, as it existed the day before March 27, 2020, counts as a final order under (b). Other regulations in effect that day setting requirements for specific OTC drugs count as final orders under (b), but only for drugs covered by (a)(1)-(4) or otherwise subject to a section 355h order. (3) FDA must withdraw the old final-monograph regulations and the old "OTC drug review" procedures (as they stood the day before March 27, 2020), or make technical fixes to keep them consistent — and can do this without normal notice-and-comment, effective on Federal Register publication or a date the notice specifies. (l) Guidance. FDA must issue guidance covering: procedures for formal meetings between FDA and sponsors/requestors; the format and content of data submissions; the format for electronic submissions; combined appeal proceedings where appropriate; and recommendations for complying with minor-change orders under (c)(3). (m) Rule of construction. (1) This section doesn't change the status of a nonprescription drug that's marketed without an approved application as of March 27, 2020, isn't subject to a section 355h order, and doesn't fall under (a)(1)-(5). (2) A drug that FDA — before March 27, 2020 — ruled ineligible for the old OTC drug review can only be legally marketed without an approved application if a section 355h order covers it. (3) Nothing here limits any other part of the drug law besides this section, and nothing stops FDA from issuing an order finding a drug not GRASE whenever it decides that's appropriate. (n) Investigational new drugs. This section doesn't apply to a drug currently covered by an investigational-use exemption under section 355(i). (o) Paperwork Reduction Act doesn't apply to information collected under this section. (p) Orders under this section follow subsection (b)'s procedures instead of the normal federal notice-and-comment rulemaking process. (q) Definitions. "Nonprescription drug" means a drug not limited to prescription-only sale. "Sponsor" means anyone who markets, makes, or processes a drug that's listed under section 360(j) and is (or will be) subject to an FDA order under this section. "Requestor" means any person or group who markets, makes, processes, or develops a drug. (r) Topical active ingredients. (1) FDA must, when deciding if a skin-applied drug's active ingredients are GRASE, allow use of real-world evidence alongside traditional clinical trial evidence as part of weighing whether benefits outweigh risks, and must apply the (b)(6)(C) safety-information rule to topical active ingredients too. (2) FDA must consider certain non-animal test types, or other appropriate alternatives to animal testing, when reviewing topical drugs, and within 1 year of November 12, 2025 must issue draft guidance on how sponsors can use non-animal alternatives to meet safety and effectiveness standards for topical drugs. (3) Nothing in this subsection changes the underlying standards for deciding whether a drug is GRASE, or the standards for judging drug safety and effectiveness generally.