21 U.S.C. § 355–1 — Risk evaluation and mitigation strategies

(a) Submission of proposed strategy (1) Initial approval: If the Secretary — after consulting the office reviewing the drug and the office handling post-approval safety — decides a risk evaluation and mitigation strategy (REMS) is needed to keep a drug's benefits ahead of its risks, and tells the applicant this, the applicant must submit a proposed REMS with the application. In deciding, the Secretary must weigh: (A) how many people are likely to use the drug; (B) how serious the disease or condition being treated is; (C) how much benefit the drug is expected to provide; (D) how long treatment is expected to last; (E) how serious any known or potential side effects are, and how common they already are in people likely to use the drug; and (F) whether the drug is a new molecular entity. (2) Postapproval requirement: (A) In general: If the Secretary already approved a covered application (even one approved before this section took effect) without requiring a REMS, the Secretary can later require one — including when acting on a supplement for a new use — if new safety information comes up and the Secretary decides a REMS is needed to keep benefits ahead of risks. (B) Submission of proposed strategy: Within 120 days after the Secretary notifies the holder of this decision, or another reasonable time the Secretary sets to protect public health, the holder must submit a proposed REMS. (3) Abbreviated new drug applications: Whether this section applies to a generic drug application under section 355(j) is governed by subsection (i). (4) Non-delegation: Only people at or above the level authorized to approve a drug (such as division directors at the Center for Drug Evaluation and Research) can make these determinations for a drug. (b) Definitions (1) "Adverse drug experience" means any bad event linked to using the drug in humans, whether or not it is actually drug-related — including one occurring during normal medical use, from an overdose (accidental or intentional), from abuse of the drug, from stopping the drug, and any failure of the drug to work as expected (which can include reduced effectiveness under the labeled directions, but not reduced effectiveness that matches what the label already says). (2) "Covered application" means an application referred to in section 355(p)(1)(A). (3) "New safety information" about a drug means information from a clinical trial, an adverse event report, a post-approval study (including one under section 355(o)(3)), peer-reviewed medical literature, data from the post-market risk system under section 355(k), or other scientific data the Secretary finds appropriate, about: (A) a serious or unexpected serious risk the Secretary has learned about since approval, since the REMS was required, or since the REMS was last assessed (this can include a new analysis of existing information); or (B) how effective the approved REMS is, learned since it was last assessed. (4) "Serious adverse drug experience" is one that either (A) results in death; an event that placed the patient at immediate risk of death as it actually occurred (not one that merely might have caused death in a more severe form); hospitalization or a longer hospital stay; a persistent or major disability; or a birth defect — or (B) that, based on appropriate medical judgment, may endanger the patient and may require medical or surgical treatment to prevent one of those outcomes. (5) "Serious risk" means a risk of a serious adverse drug experience. (6) "Signal of a serious risk" means information tied to a serious adverse drug experience associated with the drug, coming from: (A) a clinical trial; (B) adverse event reports; (C) a post-approval study, including one under section 355(o)(3); (D) peer-reviewed medical literature; (E) data from the post-market risk system under section 355(k)(4); or (F) other scientific data the Secretary finds appropriate. (7) "Responsible person" means whoever submitted the covered application, or now holds the approved application. (8) "Unexpected serious risk" means a serious adverse drug experience not listed on the drug's label — or one that may be related in symptoms or cause to something on the label, but that differs because it is more severe, more specific, or more common. (c) Contents A proposed REMS under subsection (a) must (1) include the timetable required by subsection (d), and (2), to whatever extent the Secretary requires after consulting the reviewing office and the post-approval safety office, include additional elements described in subsections (e) and (f). (d) Minimal strategy At minimum, the REMS timetable must require an assessment (1) by 18 months after the strategy is first approved; (2) by 3 years after that approval; and (3) in the seventh year after approval. (4) Beyond that: (A) assessments happen at whatever frequency the strategy specifies; (B) that frequency can be increased or reduced as allowed under subsection (g)(4)(A); and (C) assessments are eliminated after the 3-year mark described in paragraph (1) if the Secretary decides the drug's serious risks have been adequately identified, assessed, and managed. (e) Additional potential elements of strategy (1) In general: After consulting the offices described in subsection (c)(2), the Secretary may require one or more of the following extra elements — but only after making the required finding for each one. (2) Medication Guide; patient package insert: The REMS may require the responsible person to prepare, for distribution to each patient when the drug is dispensed: (A) a Medication Guide under part 208 of title 21, Code of Federal Regulations (or its successor); and (B) a patient package insert, if the Secretary decides it may help mitigate a serious risk. (3) Communication plan: The REMS may require a communication plan to health care providers, if the Secretary decides such a plan may support the strategy. This plan may include: (A) sending letters to providers; (B) sharing information about REMS elements that apply to providers, or explaining safety protocols such as periodic lab tests; (C) sharing information through professional societies about the drug's serious risks and any safe-use protocol; or (D) sharing information about drug formulations or properties, including limits on patient care from those formulations, and how they relate to serious adverse events. (4) Packaging and disposal: For a drug with a serious risk of the type of adverse experience described in subsection (b)(1)(B) or (C) — overdose or abuse — the Secretary, weighing the factors in subsection (f)(2)(C)-(D) and consulting other relevant federal agencies over drug disposal, may require: (A) that the drug be dispensed to certain patients only in unit-dose packaging, packaging with a set duration, or another packaging system that might mitigate the risk; or (B) that the drug be dispensed with safe disposal packaging or a safe disposal system, if the Secretary decides that would help mitigate the risk and is sufficiently available. (f) Providing safe access for patients to drugs with known serious risks that would otherwise be unavailable (1) Allowing safe access to drugs with known serious risks: The Secretary may require REMS elements necessary to assure safe use of a drug, given its inherent toxicity or potential harm, if the Secretary decides: (A) the drug has been shown effective but is linked to a serious adverse drug experience, and can be approved (or would otherwise be withdrawn) only if these elements are part of the strategy to mitigate that specific labeled risk; and (B) for a drug approved without such elements, the other tools under subsections (c), (d), and (e) are not enough. (2) Assuring access and minimizing burden: These "elements to assure safe use" must (A) match the seriousness of the specific labeled risk; (B) be posted publicly by the Secretary, with an explanation of how they will mitigate the risk, within 30 days of being imposed; (C) not unduly burden patient access — especially considering patients with serious or life-threatening diseases, patients who have difficulty getting health care (such as those in rural or medically underserved areas), and patients with functional limitations; and (D) where practical, match elements used for other drugs with similar serious risks, and be designed to fit existing distribution, procurement, and dispensing systems, so as to minimize the burden on the health care delivery system. (3) Elements to assure safe use: These elements must include one or more goals to mitigate the specific labeled risk, and may require: (A) that prescribing providers have particular training, experience, or certification (any willing provider from a frontier area must have access to that training or certification, including online or by mail, at reasonable cost); (B) that dispensing pharmacies, practitioners, or health care settings be specially certified (again, open to any willing frontier-area provider); (C) that the drug be dispensed to patients only in certain health care settings, such as hospitals; (D) that the drug be dispensed only with evidence of safe-use conditions, such as lab test results; (E) that each patient be subject to certain monitoring; or (F) that each patient be enrolled in a registry. (4) Implementation system: For the elements described in paragraph (3)(B)-(D), a system may let the applicant take reasonable steps to (A) monitor and evaluate how health care providers, pharmacists, and others implement the elements, and (B) work to improve that implementation. (5) Evaluation of elements to assure safe use: Through the Drug Safety and Risk Management Advisory Committee (or its successor) or another FDA advisory committee, the Secretary must (A) seek input from patients, doctors, pharmacists, and other providers on how to standardize these elements so they are not unduly burdensome on access and, where practical, minimize the burden on the health care system; (B) periodically evaluate, for one or more drugs, whether the elements assure safe use, avoid undue burden on access, and minimize system burden; and (C) based on that input and evaluation, issue or modify agency guidance on implementing this subsection, and modify the elements for one or more drugs as appropriate. (6) Additional mechanisms to assure access: The expanded-access mechanisms under section 360bbb may be used so patients with a serious or life-threatening disease or condition can get a drug for an unapproved use even though it is subject to safe-use elements under this subsection. The Secretary must issue regulations on how a physician may provide the drug this way. (7) Repealed. (8) Limitation: No holder of an approved covered application may use a required safe-use element to block or delay approval of a competing application under section 355(b)(2) or (j), or to prevent such an element from applying, under subsection (i)(1)(B), to a drug that is the subject of an abbreviated new drug application. (g) Assessment and modification of approved strategy (1) Voluntary assessments: After a REMS is approved, the responsible person may, subject to paragraph (2), submit an assessment of it to the Secretary at any time. (2) Required assessments: The responsible person must submit an assessment (A) when submitting a supplement for a new use under section 355(b) or 42 U.S.C. § 262 — unless the drug is not subject to section 353(b) and the REMS includes only the subsection (d) timetable; (B) when required by the REMS's own timetable under subsection (d); or (C) within a time set by the Secretary, if the Secretary, after consulting the offices described in subsection (c)(2), decides an assessment is needed to check whether the strategy should be modified to (i) keep the drug's benefits ahead of its risks, or (ii) reduce the burden on the health care delivery system. (3) Requirements for assessments: An assessment must address, for each goal in the strategy, whether the strategy — including each of its elements — is meeting that goal, or whether the goal or elements should be modified. (4) Modification: (A) On initiative of responsible person: After approval, the responsible person may, at any time, propose adding, modifying, or removing any goal or element, with an adequate rationale for the change. (B) On initiative of Secretary: After approval, the Secretary, after consulting the offices described in subsection (c)(2), may require the responsible person to propose a modification within 120 days (or another reasonable time the Secretary sets) if the Secretary decides one or more goals or elements should be added, modified, or removed to (i) keep benefits ahead of risks, (ii) reduce burden on the health care delivery system, or (iii) let a generic drug's safe-use elements differ, in a comparable way, from those of the listed drug it references. (h) Review of proposed strategies; review of assessments and modifications of approved strategies (1) In general: The Secretary, after consulting the offices described in subsection (c)(2), must promptly review each proposed REMS submitted under subsection (a), and each assessment of or proposed modification to an approved REMS submitted under subsection (g), and, if needed, promptly start discussions with the responsible person. (2) Action: (A) In general: (i) Timeframe: Unless dispute resolution under paragraph (3) or (4) applies, the Secretary must review and act on a proposed REMS or proposed modification within 180 days of receiving it. (ii) Minor modifications: The Secretary must review and act on a proposed "minor modification," as defined by the Secretary in guidance, within 60 days of receiving it. (iii) REMS modification due to safety labeling changes: The Secretary must review and act, within 60 days, on a proposed modification that conforms an approved REMS to an approved safety labeling change — including one the responsible person made on its own, or one the Secretary directed under section 355(o)(4). (iv) Guidance: The Secretary must establish, through guidance, that responsible persons may make certain REMS modifications simply by notifying the Secretary. (B) Inaction: If the Secretary fails to act within these deadlines, the approved REMS stays in effect until the Secretary does act. (C) Public availability: After acting on a proposed REMS or modification, the Secretary must publicly release an action letter describing the actions taken. (3) Dispute resolution at initial approval: If a proposed REMS is submitted with an initial approval application under subsection (a)(1) and there is a dispute about it, the responsible person must use the major dispute resolution procedures described in the letters referenced in section 101(c) of the FDA Amendments Act of 2007. (4) Dispute resolution in all other cases: (A) Request for review: (i) In general: After being required to make a submission under subsection (a)(2) or (g), the responsible person may request in writing that the Drug Safety Oversight Board review a dispute about the strategy — except that the Secretary's basic determination to require a REMS at all cannot be reviewed this way (though the strategy's particular elements can be). (ii) Scheduling: Once such a request is received, the Secretary must schedule the dispute for review and, within 5 business days, publish notice that the Board will review it. (B) Scheduling review: The Secretary must schedule the dispute for one of the Board's next two regular meetings, whichever is more practical, or may convene a special meeting to review it faster, including to meet an application deadline. (C) Agreement after discussion or administrative appeals: (i) Requesting review does not stop further discussion or the use of internal FDA administrative appeals to reach agreement — but once a review is scheduled and posted, the responsible person must either withdraw the review request or drop the administrative appeal. (ii) At any point before the Board issues a decision, the Secretary (after consulting the offices in subsection (c)(2)) and the responsible person may reach agreement through further discussion or appeals, ending the dispute process, with the Secretary issuing an action letter or order describing the agreed strategy. (D) Meeting of the Board: At the meeting, the Board must hear from both parties, by written or oral presentation, and review the dispute. (E) Record of proceedings: The Secretary must record and transcribe the meeting and make it public within 90 days, redacting trade secrets and other legally protected information. (F) Recommendation of the Board: Within 5 days of the meeting, the Board must give the Secretary a written recommendation; within 5 more days, the Secretary must make that recommendation public. (G) Action by the Secretary: (i) For a proposal or assessment under paragraph (1), the Secretary must issue an action letter resolving the dispute by the later of the application's action deadline or 7 days after receiving the Board's recommendation. (ii) For an assessment of an already-approved REMS under subsection (g)(1) or (g)(2)(B)-(D), the Secretary must issue a public order resolving the dispute within 7 days of receiving the recommendation. (H) Inaction: If the Secretary fails to act within these deadlines, the approved REMS stays in effect until the Secretary does act. (I) Effect on action deadline: The Secretary is treated as having met the application's action deadline as long as the responsible person requested this dispute process and the Secretary met the scheduling, recommendation, and action-letter deadlines. (J) Disqualification: An FDA employee who reviewed the drug, or who took part in an administrative appeal about it, cannot sit on the Board for a meeting reviewing a dispute about that drug's REMS. (K) Additional expertise: For a Board meeting, the Board may add members with relevant expertise — from FDA offices such as Pediatrics, Women's Health, or Rare Diseases, or from other federal health agencies. (5) Use of advisory committees: The Secretary may convene one or more FDA advisory committees to (A) review a safety concern about a drug or class of drugs, including before a REMS assessment is required under subsection (g)(2)(B) or (C); (B) review the REMS of a drug or group of drugs; or (C) review a dispute under paragraph (3) or (4). (6) Process for addressing drug class effects: (A) In general: When a serious-risk concern may relate to a drug's whole pharmacological class, the Secretary, after consulting the offices in subsection (c)(2), may delay REMS assessments for those drugs until holding one or more public meetings on possible responses. (B) Notice: If the Secretary delays an assessment this way, the Secretary must, within 5 days, notify the application holder, publish the delay in the Federal Register, and give public notice of any public meetings, including a description of the delay. (C) Public meetings: These meetings may include meetings with the responsible persons for the drugs, FDA advisory committee meetings, or workshops of scientific experts and stakeholders. (D) Action: After considering the discussions, the Secretary may announce a planned regulatory action for the drug class — including a REMS modification — in the Federal Register, seek public comment, and then issue an order addressing the action. (7) International coordination: The Secretary, after consulting the offices in subsection (c)(2), may coordinate the REMS assessment timetable under subsection (d), or a study or trial required under section 355(o)(3), with similar risk-assessment efforts by comparable foreign drug regulators, and must notify the responsible person if this coordination happens. (8) Effect: Using the class-effects process in paragraph (6) or the international-coordination process in paragraph (7) may not be the sole reason an application or supplement is delayed. (i) Abbreviated new drug applications (1) In general: A drug that is the subject of a generic (abbreviated new drug) application under section 355(j) is subject only to these elements of the listed drug's REMS: (A) a Medication Guide or patient package insert, if required under subsection (e) for the listed drug; (B) a packaging or disposal requirement, if required under subsection (e)(4) for the listed drug; and (C)(i) elements to assure safe use, if required under subsection (f) for the listed drug — which the generic drug may satisfy using either (I) a single, shared system with the listed drug, or (II) a different, comparable version of the elements to assure safe use — though (ii) the Secretary may require the generic and listed drug to use a single, shared system if the Secretary decides no different, comparable version could satisfy subsection (f). (2) Action by Secretary: For a listed drug that now has an approved generic under section 355(j), the Secretary (A) must still carry out any communication plan to providers required under subsection (e)(3) for the listed drug; (B) must permit packaging or disposal systems for the generic that differ from those required for the listed drug under subsection (e)(4); and (C) must inform the generic's responsible person if the listed drug's REMS is modified. (3) Shared REMS: If the Secretary approves a different, comparable version of the safe-use elements under paragraph (1)(C)(i)(II) for a generic drug, the Secretary may let any other generic drug referencing the same listed drug use that same different version too. (j) Drug Safety Oversight Board (1) In general: This subsection establishes a Drug Safety Oversight Board. (2) Composition; meetings: The Board must (A) be made up of scientists and health care practitioners, all federal employees, appointed by the Secretary; (B) include representatives from across the FDA, including its post-approval safety offices; (C) include at least one representative each from the National Institutes of Health and from HHS outside the FDA; (D) include representatives the Secretary designates from other agencies that want to take part; and (E) meet at least monthly to advise the Secretary on important drug safety issues. (k) Waiver in public health emergencies The Secretary may waive any requirement of this section for a "qualified countermeasure" (as defined in 42 U.S.C. § 247d–6a(a)(2)) that this section already applies to, if the waiver is needed to mitigate or reduce the severity of the circumstances behind (1) certain emergency determinations made by the Secretary of Homeland Security, the Secretary of Defense, or the Secretary under section 360bbb–3(b)(1)(A)-(C); or (2) a material threat identified under section 360bbb–3(b)(1)(D), made pursuant to 42 U.S.C. § 247d–6b. (l) Provision of samples not a violation of strategy Giving samples of a covered product to an "eligible product developer" (as those terms are defined in section 355–2(a)) is not a violation of any REMS in place for that drug. (m) Separate REMS In this section, "different, comparable aspect of the elements to assure safe use" means a REMS for a generic drug under section 355(j) that uses different methods or operational means than the strategy required under subsection (a) for the listed drug (or for another generic drug referencing the same listed drug), but that reaches the same level of safety as that strategy.