---
kind: "section"
citation: "21 U.S.C. § 355–1"
title: "21"
title_heading: "Food and Drugs"
number: "355–1"
heading: "Risk evaluation and mitigation strategies"
release: "119-102"
url: "https://uscodex.org/usc/21/355-1"
units:
  - "Chapter 9 — Federal Food, Drug, and Cosmetic Act"
  - "Subchapter V — Drugs and Devices"
  - "Part A — Drugs and Devices"
---

# §355–1. Risk evaluation and mitigation strategies

- (a) **Submission of proposed strategy—**
  - (1) **Initial approval—** If the [Secretary](/usc/21/321.md?p=d), in consultation with the [office](/usc/21/1701.md?p=14) responsible for reviewing the [drug](/usc/21/321.md?p=g-1) and the [office](/usc/21/1701.md?p=14) responsible for postapproval safety with respect to the [drug](/usc/21/321.md?p=g-1), determines that a risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) is necessary to ensure that the benefits of the [drug](/usc/21/321.md?p=g-1) outweigh the risks of the [drug](/usc/21/321.md?p=g-1), and informs the [person](/usc/21/321.md?p=e) who submits such application of such determination, then such [person](/usc/21/321.md?p=e) shall submit to the [Secretary](/usc/21/321.md?p=d) as part of such application a proposed risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12). In making such a determination, the [Secretary](/usc/21/321.md?p=d) shall consider the following factors:
    - (A) The estimated size of the population likely to use the [drug](/usc/21/321.md?p=g-1) involved.
    - (B) The seriousness of the disease or condition that is to be treated with the [drug](/usc/21/321.md?p=g-1).
    - (C) The expected benefit of the [drug](/usc/21/321.md?p=g-1) with respect to such disease or condition.
    - (D) The expected or actual duration of treatment with the [drug](/usc/21/321.md?p=g-1).
    - (E) The seriousness of any known or potential adverse events that may be related to the [drug](/usc/21/321.md?p=g-1) and the background incidence of such events in the population likely to use the [drug](/usc/21/321.md?p=g-1).
    - (F) Whether the [drug](/usc/21/321.md?p=g-1) is a new molecular entity.
  - (2) **Postapproval requirement—**
    - (A) **In general—** If the [Secretary](/usc/21/321.md?p=d) has approved a [covered application](#b-2) (including an application approved before the effective date of this section) and did not when approving the application require a risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) under [paragraph (1)](#a-1), the [Secretary](/usc/21/321.md?p=d), in consultation with the [offices](/usc/21/1701.md?p=14) described in [paragraph (1)](#a-1), may subsequently require such a [strategy](/usc/21/1701.md?p=12) for the [drug](/usc/21/321.md?p=g-1) involved (including when acting on a supplemental application seeking approval of a new indication for use of the [drug](/usc/21/321.md?p=g-1)) if the [Secretary](/usc/21/321.md?p=d) becomes aware of [new safety information](/usc/21/355.md?p=o-2-C) and makes a determination that such a [strategy](/usc/21/1701.md?p=12) is necessary to ensure that the benefits of the [drug](/usc/21/321.md?p=g-1) outweigh the risks of the [drug](/usc/21/321.md?p=g-1).
    - (B) **Submission of proposed strategy—** Not later than 120 days after the [Secretary](/usc/21/321.md?p=d) notifies the holder of an approved [covered application](#b-2) that the [Secretary](/usc/21/321.md?p=d) has made a determination under [subparagraph (A)](#a-2-A) with respect to the [drug](/usc/21/321.md?p=g-1) involved, or within such other reasonable time as the [Secretary](/usc/21/321.md?p=d) requires to protect the public health, the holder shall submit to the [Secretary](/usc/21/321.md?p=d) a proposed risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12).
  - (3) **Abbreviated new drug applications—** The applicability of this section to an application under [section 355(j) of this title](/usc/21/355.md?p=j) is subject to [subsection (i)](#i).
  - (4) **Non-delegation—** Determinations by the [Secretary](/usc/21/321.md?p=d) under this subsection for a [drug](/usc/21/321.md?p=g-1) shall be made by individuals at or above the level of individuals empowered to approve a [drug](/usc/21/321.md?p=g-1) (such as division directors within the Center for [Drug](/usc/21/321.md?p=g-1) Evaluation and Research).
- (b) **Definitions—** For purposes of this section:
  - (1) **Adverse drug experience—** The term “adverse drug experience” means any adverse event associated with the use of a [drug](/usc/21/321.md?p=g-1) in humans, whether or not considered [drug](/usc/21/321.md?p=g-1) related, including—
    - (A) an adverse event occurring in the course of the use of the [drug](/usc/21/321.md?p=g-1) in professional practice;
    - (B) an adverse event occurring from an overdose of the [drug](/usc/21/321.md?p=g-1), whether accidental or intentional;
    - (C) an adverse event occurring from abuse of the [drug](/usc/21/321.md?p=g-1);
    - (D) an adverse event occurring from withdrawal of the [drug](/usc/21/321.md?p=g-1); and
    - (E) any failure of expected pharmacological action of the [drug](/usc/21/321.md?p=g-1), which may include reduced effectiveness under the conditions of use prescribed in the [labeling](/usc/21/321.md?p=m) of such [drug](/usc/21/321.md?p=g-1), but which may not include reduced effectiveness that is in accordance with such [labeling](/usc/21/321.md?p=m).
  - (2) **Covered application—** The term “covered application” means an application referred to in [section 355(p)(1)(A) of this title](/usc/21/355.md?p=p-1-A).
  - (3) **New safety information—** The term “[new safety information](/usc/21/355.md?p=o-2-C)”, with respect to a [drug](/usc/21/321.md?p=g-1), means information derived from a clinical trial, an adverse event report, a postapproval study (including a study under [section 355(o)(3)](/usc/21/355.md?p=o-3) of this title), or peer-reviewed biomedical literature; data derived from the postmarket risk identification and analysis system under [section 355(k) of this title](/usc/21/355.md?p=k); or other scientific data deemed appropriate by the [Secretary](/usc/21/321.md?p=d) about—
    - (A) a [serious risk](#b-5) or an [unexpected serious risk](#b-8) associated with use of the [drug](/usc/21/321.md?p=g-1) that the [Secretary](/usc/21/321.md?p=d) has become aware of (that may be based on a new analysis of existing information) since the [drug](/usc/21/321.md?p=g-1) was approved, since the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) was required, or since the last assessment of the approved risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for the [drug](/usc/21/321.md?p=g-1); or
    - (B) the effectiveness of the approved risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for the [drug](/usc/21/321.md?p=g-1) obtained since the last assessment of such [strategy](/usc/21/1701.md?p=12).
  - (4) **Serious adverse drug experience—** The term “serious adverse drug experience” is an [adverse drug experience](#b-1) that—
    - (A) results in—
      - (i) death;
      - (ii) an [adverse drug experience](#b-1) that places the patient at immediate risk of death from the [adverse drug experience](#b-1) as it occurred (not including an [adverse drug experience](#b-1) that might have caused death had it occurred in a more severe form);
      - (iii) inpatient hospitalization or prolongation of existing hospitalization;
      - (iv) a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or
      - (v) a congenital anomaly or birth defect; or
    - (B) based on appropriate medical judgment, may jeopardize the patient and may require a medical or surgical intervention to prevent an outcome described under [subparagraph (A)](#b-4-A).
  - (5) **Serious risk—** The term “serious risk” means a risk of a [serious adverse drug experience](#b-4).
  - (6) **Signal of a serious risk—** The term “signal of a serious risk” means information related to a [serious adverse drug experience](#b-4) associated with use of a [drug](/usc/21/321.md?p=g-1) and derived from—
    - (A) a clinical trial;
    - (B) adverse event reports;
    - (C) a postapproval study, including a study under [section 355(o)(3)](/usc/21/355.md?p=o-3) of this title;
    - (D) peer-reviewed biomedical literature;
    - (E) data derived from the postmarket risk identification and analysis system under [section 355(k)(4) of this title](/usc/21/355.md?p=k-4); or
    - (F) other scientific data deemed appropriate by the [Secretary](/usc/21/321.md?p=d).
  - (7) **Responsible person—** The term “responsible person” means the [person](/usc/21/321.md?p=e) submitting a [covered application](#b-2) or the holder of the approved such application.
  - (8) **Unexpected serious risk—** The term “unexpected serious risk” means a [serious adverse drug experience](#b-4) that is not listed in the [labeling](/usc/21/321.md?p=m) of a [drug](/usc/21/321.md?p=g-1), or that may be symptomatically and pathophysiologically related to an [adverse drug experience](#b-1) identified in the [labeling](/usc/21/321.md?p=m), but differs from such [adverse drug experience](#b-1) because of greater severity, specificity, or prevalence.
- (c) **Contents—** A proposed risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) under [subsection (a)](#a) shall—
  - (1) include the timetable required under [subsection (d)](#d); and
  - (2) to the extent required by the [Secretary](/usc/21/321.md?p=d), in consultation with the [office](/usc/21/1701.md?p=14) responsible for reviewing the [drug](/usc/21/321.md?p=g-1) and the [office](/usc/21/1701.md?p=14) responsible for postapproval safety with respect to the [drug](/usc/21/321.md?p=g-1), include additional elements described in subsections [(e)](#e) and [(f)](#f).
- (d) **Minimal strategy—** For purposes of [subsection (c)(1)](#c-1), the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) shall require a timetable for submission of assessments of the [strategy](/usc/21/1701.md?p=12) that—
  - (1) includes an assessment, by the date that is 18 months after the [strategy](/usc/21/1701.md?p=12) is initially approved;
  - (2) includes an assessment by the date that is 3 years after the [strategy](/usc/21/1701.md?p=12) is initially approved;
  - (3) includes an assessment in the seventh year after the [strategy](/usc/21/1701.md?p=12) is so approved; and
  - (4) subject to paragraphs [(1)](#d-1), [(2)](#d-2), and [(3)](#d-3)—
    - (A) is at a frequency specified in the [strategy](/usc/21/1701.md?p=12);
    - (B) is increased or reduced in frequency as necessary as provided for in [subsection (g)(4)(A)](#g-4-A); and
    - (C) is eliminated after the 3-year period described in [paragraph (1)](#d-1) if the [Secretary](/usc/21/321.md?p=d) determines that [serious risks](#b-5) of the [drug](/usc/21/321.md?p=g-1) have been adequately identified and assessed and are being adequately managed.
- (e) **Additional potential elements of strategy—**
  - (1) **In general—** The [Secretary](/usc/21/321.md?p=d), in consultation with the [offices](/usc/21/1701.md?p=14) described in [subsection (c)(2)](#c-2), may under such subsection require that the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) include 1 or more of the additional elements described in this subsection if the [Secretary](/usc/21/321.md?p=d) makes the determination required with respect to each element involved.
  - (2) **Medication Guide; patient package insert—** The risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) may require that, as applicable, the [responsible person](#b-7) develop for [distribution](/usc/21/360eee.md?p=5) to each patient when the [drug](/usc/21/321.md?p=g-1) is dispensed—
    - (A) a Medication Guide, as provided for under [part 208 of title 21, Code of Federal Regulations](/cfr/21/part208.md) (or any successor regulations); and
    - (B) a patient package insert, if the [Secretary](/usc/21/321.md?p=d) determines that such insert may help mitigate a [serious risk](#b-5) of the [drug](/usc/21/321.md?p=g-1).
  - (3) **Communication plan—** The risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) may require that the [responsible person](#b-7) conduct a communication plan to health care providers, if, with respect to such [drug](/usc/21/321.md?p=g-1), the [Secretary](/usc/21/321.md?p=d) determines that such plan may support implementation of an element of the [strategy](/usc/21/1701.md?p=12) (including under this paragraph). Such plan may include—
    - (A) sending letters to health care providers;
    - (B) disseminating information about the elements of the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) to encourage implementation by health care providers of components that apply to such health care providers, or to explain certain safety protocols (such as medical monitoring by periodic laboratory tests)[^1]
    - (C) disseminating information to health care providers through professional societies about any [serious risks](#b-5) of the [drug](/usc/21/321.md?p=g-1) and any protocol to assure safe use; or
    - (D) disseminating information to health care providers about [drug](/usc/21/321.md?p=g-1) formulations or properties, including information about the limitations or patient care implications of such formulations or properties, and how such formulations or properties may be related to serious adverse [drug](/usc/21/321.md?p=g-1) events associated with use of the [drug](/usc/21/321.md?p=g-1).
  - (4) **Packaging and disposal—** The [Secretary](/usc/21/321.md?p=d) may require a risk evaluation mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) for which there is a [serious risk](#b-5) of an [adverse drug experience](#b-1) described in subparagraph [(B)](#b-1-B) or [(C)](#b-1-C) of subsection (b)(1), taking into consideration the factors described in subparagraphs [(C)](#f-2-C) and [(D)](#f-2-D) of subsection (f)(2) and in consultation with other relevant Federal agencies with authorities over [drug](/usc/21/321.md?p=g-1) disposal packaging, which may include requiring that—
    - (A) the [drug](/usc/21/321.md?p=g-1) be made available for dispensing to certain patients in unit dose packaging, packaging that provides a set duration, or another packaging system that the [Secretary](/usc/21/321.md?p=d) determines may mitigate such [serious risk](#b-5); or
    - (B) the [drug](/usc/21/321.md?p=g-1) be dispensed to certain patients with a safe disposal packaging or safe disposal system if the [Secretary](/usc/21/321.md?p=d) determines that such safe disposal packaging or system may mitigate such [serious risk](#b-5) 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](/usc/21/321.md?p=d), in consultation with the [offices](/usc/21/1701.md?p=14) described in [subsection (c)(2)](#c-2), may require that the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) include such elements as are necessary to assure safe use of the [drug](/usc/21/321.md?p=g-1), because of its inherent toxicity or potential harmfulness, if the [Secretary](/usc/21/321.md?p=d) determines that—
    - (A) the [drug](/usc/21/321.md?p=g-1), which has been shown to be effective, but is associated with a [serious adverse drug experience](#b-4), can be approved only if, or would be withdrawn unless, such elements are required as part of such [strategy](/usc/21/1701.md?p=12) to mitigate a specific [serious risk](#b-5) listed in the [labeling](/usc/21/321.md?p=m) of the [drug](/usc/21/321.md?p=g-1); and
    - (B) for a [drug](/usc/21/321.md?p=g-1) initially approved without elements to assure safe use, other elements under subsections [(c)](#c), [(d)](#d), and [(e)](#e) are not sufficient to mitigate such [serious risk](#b-5).
  - (2) **Assuring access and minimizing burden—** Such elements to assure safe use under [paragraph (1)](#f-1) shall—
    - (A) be commensurate with the specific [serious risk](#b-5) listed in the [labeling](/usc/21/321.md?p=m) of the [drug](/usc/21/321.md?p=g-1);
    - (B) within 30 days of the date on which any element under [paragraph (1)](#f-1) is imposed, be posted publicly by the [Secretary](/usc/21/321.md?p=d) with an explanation of how such elements will mitigate the observed safety risk;
    - (C) considering such risk, not be unduly burdensome on patient access to the [drug](/usc/21/321.md?p=g-1), considering in particular—
      - (i) patients with serious or life-threatening diseases or conditions;
      - (ii) patients who have difficulty accessing health care (such as patients in rural or medically underserved areas); and
      - (iii) patients with functional limitations; and
    - (D) to the extent practicable, so as to minimize the burden on the health care delivery system—
      - (i) conform with elements to assure safe use for other [drugs](/usc/21/321.md?p=g-1) with similar, [serious risks](#b-5); and
      - (ii) be designed to be compatible with established [distribution](/usc/21/360eee.md?p=5), procurement, and dispensing systems for [drugs](/usc/21/321.md?p=g-1).
  - (3) **Elements to assure safe use—** The elements to assure safe use under [paragraph (1)](#f-1) shall include 1 or more goals to mitigate a specific [serious risk](#b-5) listed in the [labeling](/usc/21/321.md?p=m) of the [drug](/usc/21/321.md?p=g-1) and, to mitigate such risk, may require that—
    - (A) health care providers who prescribe the [drug](/usc/21/321.md?p=g-1) have particular training or experience, or are specially certified (the opportunity to obtain such training or certification with respect to the [drug](/usc/21/321.md?p=g-1) shall be available to any willing provider from a frontier area in a widely available training or certification method (including an on-line course or via mail) as approved by the [Secretary](/usc/21/321.md?p=d) at reasonable cost to the provider);
    - (B) pharmacies, practitioners, or health care settings that dispense the [drug](/usc/21/321.md?p=g-1) are specially certified (the opportunity to obtain such certification shall be available to any willing provider from a frontier area);
    - (C) the [drug](/usc/21/321.md?p=g-1) be dispensed to patients only in certain health care settings, such as hospitals;
    - (D) the [drug](/usc/21/321.md?p=g-1) be dispensed to patients with evidence or other documentation of safe-use conditions, such as laboratory test results;
    - (E) each patient using the [drug](/usc/21/321.md?p=g-1) be subject to certain monitoring; or
    - (F) each patient using the [drug](/usc/21/321.md?p=g-1) be enrolled in a registry.
  - (4) **Implementation system—** The elements to assure safe use under [paragraph (1)](#f-1) that are described in subparagraphs [(B)](#f-3-B), [(C)](#f-3-C), and [(D)](#f-3-D) of paragraph (3) may include a system through which the applicant is able to take reasonable steps to—
    - (A) monitor and evaluate implementation of such elements by health care providers, pharmacists, and other parties in the health care system who are responsible for implementing such elements; and
    - (B) work to improve implementation of such elements by such [persons](/usc/21/321.md?p=e).
  - (5) **Evaluation of elements to assure safe use—** The [Secretary](/usc/21/321.md?p=d), through the [Drug](/usc/21/321.md?p=g-1) Safety and Risk Management Advisory Committee (or successor committee) or other advisory committee of the [Food](/usc/21/321.md?p=f) and [Drug](/usc/21/321.md?p=g-1) Administration, shall—
    - (A) seek input from patients, physicians, pharmacists, and other health care providers about how elements to assure safe use under this subsection for 1 or more [drugs](/usc/21/321.md?p=g-1) may be standardized so as not to be—
      - (i) unduly burdensome on patient access to the [drug](/usc/21/321.md?p=g-1); and
      - (ii) to the extent practicable, minimize[^2] the burden on the health care delivery system;
    - (B) periodically evaluate, for 1 or more [drugs](/usc/21/321.md?p=g-1), the elements to assure safe use of such [drug](/usc/21/321.md?p=g-1) to assess whether the elements—
      - (i) assure safe use of the [drug](/usc/21/321.md?p=g-1);
      - (ii) are not unduly burdensome on patient access to the [drug](/usc/21/321.md?p=g-1); and
      - (iii) to the extent practicable, minimize the burden on the health care delivery system; and
    - (C) considering such input and evaluations—
      - (i) issue or modify agency guidance about how to implement the requirements of this subsection; and
      - (ii) modify elements under this subsection for 1 or more [drugs](/usc/21/321.md?p=g-1) as appropriate.
  - (6) **Additional mechanisms to assure access—** The mechanisms under [section 360bbb of this title](/usc/21/360bbb.md) to provide for expanded access for patients with serious or life-threatening diseases or conditions may be used to provide access for patients with a serious or life-threatening disease or condition, the treatment of which is not an approved use for the [drug](/usc/21/321.md?p=g-1), to a [drug](/usc/21/321.md?p=g-1) that is subject to elements to assure safe use under this subsection. The [Secretary](/usc/21/321.md?p=d) shall promulgate regulations for how a physician may provide the [drug](/usc/21/321.md?p=g-1) under the mechanisms of [section 360bbb of this title](/usc/21/360bbb.md).
  - (7) **Repealed. Pub. L. 113–5, title III, § 302(c)(1), Mar. 13, 2013, 127 Stat. 185—**
  - (8) **Limitation—** No holder of an approved [covered application](#b-2) shall use any element to assure safe use required by the [Secretary](/usc/21/321.md?p=d) under this subsection to block or delay approval of an application under section [355(b)(2)](/usc/21/355.md?p=b-2) or [(j)](/usc/21/355.md?p=j) of this title or to prevent application of such element under [subsection (i)(1)(B)](#i-1-B) to a [drug](/usc/21/321.md?p=g-1) that is the subject of an abbreviated [new drug](/usc/21/321.md?p=p) application.
- (g) **Assessment and modification of approved strategy—**
  - (1) **Voluntary assessments—** After the approval of a risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) under [subsection (a)](#a), the [responsible person](#b-7) involved may, subject to [paragraph (2)](#g-2), submit to the [Secretary](/usc/21/321.md?p=d) an assessment of the approved [strategy](/usc/21/1701.md?p=12) for the [drug](/usc/21/321.md?p=g-1) involved at any time.
  - (2) **Required assessments—** A [responsible person](#b-7) shall submit an assessment of the approved risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1)—
    - (A) when submitting a supplemental application for a new indication for use under [section 355(b) of this title](/usc/21/355.md?p=b) or under [section 262 of title 42](/usc/42/262.md), unless the [drug](/usc/21/321.md?p=g-1) is not subject to [section 353(b) of this title](/usc/21/353.md?p=b) and the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for the [drug](/usc/21/321.md?p=g-1) includes only the timetable under [subsection (d)](#d);
    - (B) when required by the [strategy](/usc/21/1701.md?p=12), as provided for in such timetable under [subsection (d)](#d);
    - (C) within a time period to be determined by the [Secretary](/usc/21/321.md?p=d), if the [Secretary](/usc/21/321.md?p=d), in consultation with the [offices](/usc/21/1701.md?p=14) described in [subsection (c)(2)](#c-2), determines that an assessment is needed to evaluate whether the approved [strategy](/usc/21/1701.md?p=12) should be modified to—
      - (i) ensure the benefits of the [drug](/usc/21/321.md?p=g-1) outweigh the risks of the [drug](/usc/21/321.md?p=g-1); or
      - (ii) minimize the burden on the health care delivery system of complying with the [strategy](/usc/21/1701.md?p=12).
  - (3) **Requirements for assessments—** An assessment under paragraph [(1)](#g-1) or [(2)](#g-2) of an approved risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) shall include, with respect to each goal included in the [strategy](/usc/21/1701.md?p=12), an assessment of the extent to which the approved [strategy](/usc/21/1701.md?p=12), including each element of the [strategy](/usc/21/1701.md?p=12), is meeting the goal or whether 1 or more such goals or such elements should be modified.
  - (4) **Modification—**
    - (A) **On initiative of responsible person—** After the approval of a risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) by the [Secretary](/usc/21/321.md?p=d), the [responsible person](#b-7) may, at any time, submit to the [Secretary](/usc/21/321.md?p=d) a proposal to modify the approved [strategy](/usc/21/1701.md?p=12). Such proposal may propose the addition, modification, or removal of any goal or element of the approved [strategy](/usc/21/1701.md?p=12) and shall include an adequate rationale to support such proposed addition, modification, or removal of any goal or element of the [strategy](/usc/21/1701.md?p=12).
    - (B) **On initiative of Secretary—** After the approval of a risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) by the [Secretary](/usc/21/321.md?p=d), the [Secretary](/usc/21/321.md?p=d) may, at any time, require a [responsible person](#b-7) to submit a proposed modification to the [strategy](/usc/21/1701.md?p=12) within 120 days or within such reasonable time as the [Secretary](/usc/21/321.md?p=d) specifies, if the [Secretary](/usc/21/321.md?p=d), in consultation with the [offices](/usc/21/1701.md?p=14) described in [subsection (c)(2)](#c-2), determines that 1 or more goals or elements should be added, modified, or removed from the approved [strategy](/usc/21/1701.md?p=12) to—
      - (i) ensure the benefits of the [drug](/usc/21/321.md?p=g-1) outweigh the risks of the [drug](/usc/21/321.md?p=g-1);
      - (ii) minimize the burden on the health care delivery system of complying with the [strategy](/usc/21/1701.md?p=12); or
      - (iii) accommodate different, comparable aspects of the elements to assure safe use for a [drug](/usc/21/321.md?p=g-1) that is the subject of an application under [section 355(j) of this title](/usc/21/355.md?p=j), and the applicable listed [drug](/usc/21/321.md?p=g-1).
- (h) **Review of proposed strategies; review of assessments and modifications of approved strategies—**
  - (1) **In general—** The [Secretary](/usc/21/321.md?p=d), in consultation with the [offices](/usc/21/1701.md?p=14) described in [subsection (c)(2)](#c-2), shall promptly review each proposed risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) submitted under [subsection (a)](#a) and each assessment of and proposed modification to an approved risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) submitted under [subsection (g)](#g), and, if necessary, promptly initiate discussions with the [responsible person](#b-7) about such proposed [strategy](/usc/21/1701.md?p=12), assessment, or modification.
  - (2) **Action—**
    - (A) **In general—**
      - (i) **Timeframe—** Unless the dispute resolution process described under paragraph [(3)](#h-3) or [(4)](#h-4) applies, and, except as provided in [clause (ii)](#h-2-A-ii) or [clause (iii)](#h-2-A-iii) below, the [Secretary](/usc/21/321.md?p=d), in consultation with the [offices](/usc/21/1701.md?p=14) described in [subsection (c)(2)](#c-2), shall review and act on the proposed risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) or any proposed modification to any required [strategy](/usc/21/1701.md?p=12) within 180 days of receipt of the proposed [strategy](/usc/21/1701.md?p=12) or modification.
      - (ii) **Minor modifications—** The [Secretary](/usc/21/321.md?p=d) shall review and act on a proposed minor modification, as defined by the [Secretary](/usc/21/321.md?p=d) in guidance, within 60 days of receipt of such modification.
      - (iii) **REMS modification due to safety labeling changes—** Not later than 60 days after the [Secretary](/usc/21/321.md?p=d) receives a proposed modification to an approved risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) to conform the [strategy](/usc/21/1701.md?p=12) to approved safety [labeling](/usc/21/321.md?p=m) changes, including safety [labeling](/usc/21/321.md?p=m) changes initiated by the [responsible person](#b-7) in accordance with FDA regulatory requirements, or to a safety [labeling](/usc/21/321.md?p=m) change that the [Secretary](/usc/21/321.md?p=d) has directed the holder of the application to make pursuant to [section 355(o)(4)](/usc/21/355.md?p=o-4) of this title, the [Secretary](/usc/21/321.md?p=d) shall review and act on such proposed modification to the approved [strategy](/usc/21/1701.md?p=12).
      - (iv) **Guidance—** The [Secretary](/usc/21/321.md?p=d) shall establish, through guidance, that [responsible persons](#b-7) may implement certain modifications to an approved risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) following notification to the [Secretary](/usc/21/321.md?p=d).
    - (B) **Inaction—** An approved risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) shall remain in effect until the [Secretary](/usc/21/321.md?p=d) acts, if the [Secretary](/usc/21/321.md?p=d) fails to act as provided under [subparagraph (A)](#h-2-A).
    - (C) **Public availability—** Upon acting on a proposed risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) or proposed modification to a risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) under [subparagraph (A)](#h-2-A), the [Secretary](/usc/21/321.md?p=d) shall make publicly available an action letter describing the actions taken by the [Secretary](/usc/21/321.md?p=d) under such [subparagraph (A)](#h-2-A).
  - (3) **Dispute resolution at initial approval—** If a proposed risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) is submitted under [subsection (a)(1)](#a-1) in an application for initial approval of a [drug](/usc/21/321.md?p=g-1) and there is a dispute about the [strategy](/usc/21/1701.md?p=12), the [responsible person](#b-7) shall use the major dispute resolution procedures as set forth in the letters described in [section 101(c)](/usc/21/101.md) of the [Food](/usc/21/321.md?p=f) and [Drug](/usc/21/321.md?p=g-1) Administration Amendments Act of 2007.
  - (4) **Dispute resolution in all other cases—**
    - (A) **Request for review—**
      - (i) **In general—** The [responsible person](#b-7) may, after the [sponsor](/usc/21/379j–71.md?p=13) is required to make a submission under subsection [(a)(2)](#a-2) or [(g)](#g), request in writing that a dispute about the [strategy](/usc/21/1701.md?p=12) be reviewed by the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board under [subsection (j)](#j), except that the determination of the [Secretary](/usc/21/321.md?p=d) to require a risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) is not subject to review under this paragraph. The preceding sentence does not prohibit review under this paragraph of the particular elements of such a [strategy](/usc/21/1701.md?p=12).
      - (ii) **Scheduling—** Upon receipt of a request under [clause (i)](#h-4-A-i), the [Secretary](/usc/21/321.md?p=d) shall schedule the dispute involved for review under [subparagraph (B)](#h-4-B) and, not later than 5 business days of[^3] scheduling the dispute for review, shall publish by posting on the Internet or otherwise a notice that the dispute will be reviewed by the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board.
    - (B) **Scheduling review—** If a [responsible person](#b-7) requests review under [subparagraph (A)](#h-4-A), the [Secretary](/usc/21/321.md?p=d)—
      - (i) shall schedule the dispute for review at 1 of the next 2 regular meetings of the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board, whichever meeting date is more practicable; or
      - (ii) may convene a special meeting of the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board to review the matter more promptly, including to meet an action deadline on an application (including a supplemental application).
    - (C) **Agreement after discussion or administrative appeals—**
      - (i) **Further discussion or administrative appeals—** A request for review under [subparagraph (A)](#h-4-A) shall not preclude further discussions to reach agreement on the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12), and such a request shall not preclude the use of administrative appeals within the [Food](/usc/21/321.md?p=f) and [Drug](/usc/21/321.md?p=g-1) Administration to reach agreement on the [strategy](/usc/21/1701.md?p=12), including appeals as described in the letters described in [section 101(c)](/usc/21/101.md) of the [Food](/usc/21/321.md?p=f) and [Drug](/usc/21/321.md?p=g-1) Administration Amendments Act of 2007 for procedural or scientific matters involving the review of [human drug applications](/usc/21/360bbb–4a.md?p=a-1) and supplemental applications that cannot be resolved at the divisional level. At the time a review has been scheduled under [subparagraph (B)](#h-4-B) and notice of such review has been posted, the [responsible person](#b-7) shall either withdraw the request under [subparagraph (A)](#h-4-A) or terminate the use of such administrative appeals.
      - (ii) **Agreement terminates dispute resolution—** At any time before a decision and order is issued under [subparagraph (G)](#h-4-G), the [Secretary](/usc/21/321.md?p=d) (in consultation with the [offices](/usc/21/1701.md?p=14) described in [subsection (c)(2)](#c-2)) and the [responsible person](#b-7) may reach an agreement on the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) through further discussion or administrative appeals, terminating the dispute resolution process, and the [Secretary](/usc/21/321.md?p=d) shall issue an action letter or order, as appropriate, that describes the [strategy](/usc/21/1701.md?p=12).
    - (D) **Meeting of the Board—** At a meeting of the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board described in [subparagraph (B)](#h-4-B), the Board shall—
      - (i) hear from both parties via written or oral presentation; and
      - (ii) review the dispute.
    - (E) **Record of proceedings—** The [Secretary](/usc/21/321.md?p=d) shall ensure that the proceedings of any such meeting are recorded, transcribed, and made public within 90 days of the meeting. The [Secretary](/usc/21/321.md?p=d) shall redact the transcript to protect any trade secrets and other information that is exempted from disclosure under [section 552 of title 5](/usc/5/552.md) or [section 552a of title 5](/usc/5/552a.md).
    - (F) **Recommendation of the Board—** Not later than 5 days after any such meeting, the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board shall provide a written recommendation on resolving the dispute to the [Secretary](/usc/21/321.md?p=d). Not later than 5 days after the Board provides such written recommendation to the [Secretary](/usc/21/321.md?p=d), the [Secretary](/usc/21/321.md?p=d) shall make the recommendation available to the public.
    - (G) **Action by the Secretary—**
      - (i) **Action letter—** With respect to a proposal or assessment referred to in [paragraph (1)](#h-1), the [Secretary](/usc/21/321.md?p=d) shall issue an action letter that resolves the dispute not later than the later of—
        - (I) the action deadline for the action letter on the application; or
        - (II) 7 days after receiving the recommendation of the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board.
      - (ii) **Order—** With respect to an assessment of an approved risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) under [subsection (g)(1)](#g-1) or under any of [subparagraphs (B) through (D)](#g-2-B..g-2-D) of subsection (g)(2), the [Secretary](/usc/21/321.md?p=d) shall issue an order, which shall be made public, that resolves the dispute not later than 7 days after receiving the recommendation of the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board.
    - (H) **Inaction—** An approved risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) shall remain in effect until the [Secretary](/usc/21/321.md?p=d) acts, if the [Secretary](/usc/21/321.md?p=d) fails to act as provided for under [subparagraph (G)](#h-4-G).
    - (I) **Effect on action deadline—** With respect to a proposal or assessment referred to in [paragraph (1)](#h-1), the [Secretary](/usc/21/321.md?p=d) shall be considered to have met the action deadline for the action letter on the application if the [responsible person](#b-7) requests the dispute resolution process described in this paragraph and if the [Secretary](/usc/21/321.md?p=d) has complied with the timing requirements of scheduling review by the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board, providing a written recommendation, and issuing an action letter under subparagraphs [(B)](#h-4-B), [(F)](#h-4-F), and [(G)](#h-4-G), respectively.
    - (J) **Disqualification—** No individual who is an employee of the [Food](/usc/21/321.md?p=f) and [Drug](/usc/21/321.md?p=g-1) Administration and who [reviews](/usc/21/353.md?p=iii-9-D) a [drug](/usc/21/321.md?p=g-1) or who participated in an administrative appeal under [subparagraph (C)(i)](#h-4-C-i) with respect to such [drug](/usc/21/321.md?p=g-1) may serve on the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board at a meeting under [subparagraph (D)](#h-4-D) to review a dispute about the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for such [drug](/usc/21/321.md?p=g-1).
    - (K) **Additional expertise—** The [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board may add members with relevant expertise from the [Food](/usc/21/321.md?p=f) and [Drug](/usc/21/321.md?p=g-1) Administration, including the [Office](/usc/21/1701.md?p=14) of Pediatrics, the [Office](/usc/21/1701.md?p=14) of Women’s Health, or the [Office](/usc/21/1701.md?p=14) of Rare Diseases, or from other Federal public health or health care agencies, for a meeting under [subparagraph (D)](#h-4-D) of the [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board.
  - (5) **Use of advisory committees—** The [Secretary](/usc/21/321.md?p=d) may convene a meeting of 1 or more advisory committees of the [Food](/usc/21/321.md?p=f) and [Drug](/usc/21/321.md?p=g-1) Administration to—
    - (A) review a concern about the safety of a [drug](/usc/21/321.md?p=g-1) or class of [drugs](/usc/21/321.md?p=g-1), including before an assessment of the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) or [strategies](/usc/21/1701.md?p=12) of such [drug](/usc/21/321.md?p=g-1) or [drugs](/usc/21/321.md?p=g-1) is required to be submitted under subparagraph [(B)](#g-2-B) or [(C)](#g-2-C) of subsection (g)(2);
    - (B) review the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) or [strategies](/usc/21/1701.md?p=12) of a [drug](/usc/21/321.md?p=g-1) or group of [drugs](/usc/21/321.md?p=g-1); or
    - (C) review a dispute under paragraph [(3)](#h-3) or [(4)](#h-4).
  - (6) **Process for addressing drug class effects—**
    - (A) **In general—** When a concern about a [serious risk](#b-5) of a [drug](/usc/21/321.md?p=g-1) may be related to the pharmacological class of the [drug](/usc/21/321.md?p=g-1), the [Secretary](/usc/21/321.md?p=d), in consultation with the [offices](/usc/21/1701.md?p=14) described in [subsection (c)(2)](#c-2), may defer assessments of the approved risk evaluation and mitigation [strategies](/usc/21/1701.md?p=12) for such [drugs](/usc/21/321.md?p=g-1) until the [Secretary](/usc/21/321.md?p=d) has convened 1 or more public meetings to consider possible responses to such concern.
    - (B) **Notice—** If the [Secretary](/usc/21/321.md?p=d) defers an assessment under [subparagraph (A)](#h-6-A), the [Secretary](/usc/21/321.md?p=d) shall—
      - (i) give notice of the deferral to the holder of the approved [covered application](#b-2) not later than 5 days after the deferral;
      - (ii) publish the deferral in the Federal Register; and
      - (iii) give notice to the public of any public meetings to be convened under [subparagraph (A)](#h-6-A), including a description of the deferral.
    - (C) **Public meetings—** Such public meetings may include—
      - (i) 1 or more meetings of the [responsible person](#b-7) for such [drugs](/usc/21/321.md?p=g-1);
      - (ii) 1 or more meetings of 1 or more advisory committees of the [Food](/usc/21/321.md?p=f) and [Drug](/usc/21/321.md?p=g-1) Administration, as provided for under [paragraph (6)](#h-6);[^4] or
      - (iii) 1 or more workshops of scientific experts and other stakeholders.
    - (D) **Action—** After considering the discussions from any meetings under [subparagraph (A)](#h-6-A), the [Secretary](/usc/21/321.md?p=d) may—
      - (i) announce in the Federal Register a planned regulatory action, including a modification to each risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12), for [drugs](/usc/21/321.md?p=g-1) in the pharmacological class;
      - (ii) seek public comment about such action; and
      - (iii) after seeking such comment, issue an order addressing such regulatory action.
  - (7) **International coordination—** The [Secretary](/usc/21/321.md?p=d), in consultation with the [offices](/usc/21/1701.md?p=14) described in [subsection (c)(2)](#c-2), may coordinate the timetable for submission of assessments under [subsection (d)](#d), or a study or clinical trial under [section 355(o)(3)](/usc/21/355.md?p=o-3) of this title, with efforts to identify and assess the [serious risks](#b-5) of such [drug](/usc/21/321.md?p=g-1) by the marketing authorities of other countries whose [drug](/usc/21/321.md?p=g-1) approval and risk management processes the [Secretary](/usc/21/321.md?p=d) deems comparable to the [drug](/usc/21/321.md?p=g-1) approval and risk management processes of the United States. If the [Secretary](/usc/21/321.md?p=d) takes action to coordinate such timetable, the [Secretary](/usc/21/321.md?p=d) shall give notice to the [responsible person](#b-7).
  - (8) **Effect—** Use of the processes described in paragraphs [(6)](#h-6) and [(7)](#h-7) shall not be the sole source of delay of action on an application or a supplement to an application for a [drug](/usc/21/321.md?p=g-1).
- (i) **Abbreviated new drug applications—**
  - (1) **In general—** A [drug](/usc/21/321.md?p=g-1) that is the subject of an abbreviated [new drug](/usc/21/321.md?p=p) application under [section 355(j) of this title](/usc/21/355.md?p=j) is subject to only the following elements of the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) required under [subsection (a)](#a) for the applicable listed [drug](/usc/21/321.md?p=g-1):
    - (A) A Medication Guide or patient package insert, if required under [subsection (e)](#e) for the applicable listed [drug](/usc/21/321.md?p=g-1).
    - (B) A packaging or disposal requirement, if required under [subsection (e)(4)](#e-4) for the applicable listed [drug](/usc/21/321.md?p=g-1).
    - (C)
      - (i) Elements to assure safe use, if required under [subsection (f)](#f) for the listed [drug](/usc/21/321.md?p=g-1), which, subject to [clause (ii)](#i-1-C-ii), for a [drug](/usc/21/321.md?p=g-1) that is the subject of an application under [section 355(j) of this title](/usc/21/355.md?p=j) may use—
        - (I) a single, shared system with the listed [drug](/usc/21/321.md?p=g-1) under [subsection (f)](#f); or
        - (II) a [different, comparable aspect of the elements to assure safe use](#m) under [subsection (f)](#f).
      - (ii) The [Secretary](/usc/21/321.md?p=d) may require a [drug](/usc/21/321.md?p=g-1) that is the subject of an application under [section 355(j) of this title](/usc/21/355.md?p=j) and the listed [drug](/usc/21/321.md?p=g-1) to use a single, shared system under [subsection (f)](#f), if the [Secretary](/usc/21/321.md?p=d) determines that no [different, comparable aspect of the elements to assure safe use](#m) could satisfy the requirements of [subsection (f)](#f).
  - (2) **Action by Secretary—** For an applicable listed [drug](/usc/21/321.md?p=g-1) for which a [drug](/usc/21/321.md?p=g-1) is approved under [section 355(j) of this title](/usc/21/355.md?p=j), the [Secretary](/usc/21/321.md?p=d)—
    - (A) shall undertake any communication plan to health care providers required under [subsection (e)(3)](#e-3) for the applicable listed [drug](/usc/21/321.md?p=g-1);
    - (B) shall permit packaging systems and safe disposal packaging or safe disposal systems that are different from those required for the applicable listed [drug](/usc/21/321.md?p=g-1) under [subsection (e)(4)](#e-4); and
    - (C) shall inform the [responsible person](#b-7) for the [drug](/usc/21/321.md?p=g-1) that is so approved if the risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for the applicable listed [drug](/usc/21/321.md?p=g-1) is modified.
  - (3) **Shared REMS—** If the [Secretary](/usc/21/321.md?p=d) approves, in accordance with [paragraph (1)(C)(i)(II)](#i-1-C-i-II), a [different, comparable aspect of the elements to assure safe use](#m) under [subsection (f)](#f) for a [drug](/usc/21/321.md?p=g-1) that is the subject of an abbreviated [new drug](/usc/21/321.md?p=p) application under [section 355(j) of this title](/usc/21/355.md?p=j), the [Secretary](/usc/21/321.md?p=d) may require that such different comparable aspect of the elements to assure safe use can be used with respect to any other [drug](/usc/21/321.md?p=g-1) that is the subject of an application under section [355(j)](/usc/21/355.md?p=j) or [355(b)](/usc/21/355.md?p=b) of this title that references the same listed [drug](/usc/21/321.md?p=g-1).
- (j) **Drug Safety Oversight Board—**
  - (1) **In general—** There is established a [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board.
  - (2) **Composition; meetings—** The [Drug](/usc/21/321.md?p=g-1) Safety Oversight Board shall—
    - (A) be composed of scientists and health care practitioners appointed by the [Secretary](/usc/21/321.md?p=d), each of whom is an employee of the Federal Government;
    - (B) include representatives from [offices](/usc/21/1701.md?p=14) throughout the [Food](/usc/21/321.md?p=f) and [Drug](/usc/21/321.md?p=g-1) Administration, including the [offices](/usc/21/1701.md?p=14) responsible for postapproval safety of [drugs](/usc/21/321.md?p=g-1);
    - (C) include at least 1 representative each from the National Institutes of Health and the [Department](/usc/21/321.md?p=c) of Health and Human Services (other than the [Food](/usc/21/321.md?p=f) and [Drug](/usc/21/321.md?p=g-1) Administration);
    - (D) include such representatives as the [Secretary](/usc/21/321.md?p=d) shall designate from other appropriate agencies that wish to provide representatives; and
    - (E) meet at least monthly to provide oversight and advice to the [Secretary](/usc/21/321.md?p=d) on the management of important [drug](/usc/21/321.md?p=g-1) safety issues.
- (k) **Waiver in public health emergencies—** The [Secretary](/usc/21/321.md?p=d) may waive any requirement of this section with respect to a [qualified](/usc/21/357.md?p=e-7) countermeasure (as defined in [section 247d–6a(a)(2) of title 42](/usc/42/247d–6a.md?p=a-2)) to which a requirement under this section has been applied, if the [Secretary](/usc/21/321.md?p=d) determines that such waiver is required to mitigate the effects of, or reduce the severity of, the circumstances under which—
  - (1) a determination described in subparagraph (A), (B), or (C) of [section 360bbb–3(b)(1) of this title](/usc/21/360bbb–3.md?p=b-1) has been made by the [Secretary](/usc/21/321.md?p=d) of Homeland Security, the [Secretary](/usc/21/321.md?p=d) of Defense, or the [Secretary](/usc/21/321.md?p=d), respectively; or
  - (2) the identification of a material threat described in subparagraph (D) of [section 360bbb–3(b)(1) of this title](/usc/21/360bbb–3.md?p=b-1) has been made pursuant to [section 247d–6b of title 42](/usc/42/247d–6b.md).
- (l) **Provision of samples not a violation of strategy—** The provision of samples of a covered [product](/usc/21/360eee.md?p=13) to an [eligible product developer](/usc/21/355–2.md?p=a-4) (as those terms are defined in [section 355–2(a) of this title](/usc/21/355–2.md?p=a)) shall not be considered a violation of the requirements of any risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) that may be in place under this section for such [drug](/usc/21/321.md?p=g-1).
- (m) **Separate REMS—** When used in this section, the term “different, comparable aspect of the elements to assure safe use” means a risk evaluation and mitigation [strategy](/usc/21/1701.md?p=12) for a [drug](/usc/21/321.md?p=g-1) that is the subject of an application under [section 355(j) of this title](/usc/21/355.md?p=j) that uses different methods or operational means than the [strategy](/usc/21/1701.md?p=12) required under [subsection (a)](#a) for the applicable listed [drug](/usc/21/321.md?p=g-1), or other application under [section 355(j) of this title](/usc/21/355.md?p=j) with the same such listed [drug](/usc/21/321.md?p=g-1), but achieves the same level of safety as such [strategy](/usc/21/1701.md?p=12).

## Footnotes

[^1]: So in original. Probably should be followed by a semicolon.
[^2]: So in original. Does not follow from introductory provisions.
[^3]: So in original.
[^4]: See References in Text note below.

## Source credit

(June 25, 1938, ch. 675, § 505–1, as added Pub. L. 110–85, title IX, § 901(b), Sept. 27, 2007, 121 Stat. 926; amended Pub. L. 112–144, title XI, § 1132(a), (b), July 9, 2012, 126 Stat. 1119, 1120; Pub. L. 113–5, title III, § 302(c), Mar. 13, 2013, 127 Stat. 185; Pub. L. 114–255, div. A, title III, §§ 3075(c), 3101(a)(2)(C), Dec. 13, 2016, 130 Stat. 1139, 1153; Pub. L. 115–52, title VI, § 606, Aug. 18, 2017, 131 Stat. 1049; Pub. L. 115–271, title III, §§ 3032(a)–(c), 3041(a), Oct. 24, 2018, 132 Stat. 3940–3942; Pub. L. 116–94, div. N, title I, § 610(d), (f), Dec. 20, 2019, 133 Stat. 3135, 3136; Pub. L. 117–328, div. FF, title III, § 3221, Dec. 29, 2022, 136 Stat. 5829.)

## Notes

### Editorial Notes

### References in Text

For the effective date of this section, referred to in subsec. (a)(2)(A), see Effective Date note below.

Section 101(c) of the Food and Drug Administration Amendments Act of 2007, referred to in subsec. (h)(3), (4)(C)(i), is section 101(c) of Pub. L. 110–85, which is set out as a note under section 379g of this title.

Paragraph (6), referred to in subsec. (h)(6)(C)(ii), was redesignated par. (5) of subsec. (h) of this section by Pub. L. 112–144, title XI, § 1132(b)(4), July 9, 2012, 126 Stat. 1120.

### Amendments

2022—Subsec. (e)(4)(B). Pub. L. 117–328 struck out “for purposes of rendering drugs nonretrievable (as defined in section 1300.05 of title 21, Code of Federal Regulations (or any successor regulation))” before “if the Secretary determines”.

2019—Subsec. (g)(4)(B)(iii). Pub. L. 116–94, § 610(f)(1), added cl. (iii).

Subsec. (i)(1)(C). Pub. L. 116–94, § 610(f)(2), added subpar. (C) and struck out former subpar. (C) which read as follows: “Elements to assure safe use, if required under subsection (f) for the listed drug. A drug that is the subject of an abbreviated new drug application and the listed drug shall use a single, shared system under subsection (f). The Secretary may waive the requirement under the preceding sentence for a drug that is the subject of an abbreviated new drug application, and permit the applicant to use a different, comparable aspect of the elements to assure safe use, if the Secretary determines that—

“(i) the burden of creating a single, shared system outweighs the benefit of a single, system, taking into consideration the impact on health care providers, patients, the applicant for the abbreviated new drug application, and the holder of the reference drug product; or

“(ii) an aspect of the elements to assure safe use for the applicable listed drug is claimed by a patent that has not expired or is a method or process that, as a trade secret, is entitled to protection, and the applicant for the abbreviated new drug application certifies that it has sought a license for use of an aspect of the elements to assure safe use for the applicable listed drug and that it was unable to obtain a license.

A certification under clause (ii) shall include a description of the efforts made by the applicant for the abbreviated new drug application to obtain a license. In a case described in clause (ii), the Secretary may seek to negotiate a voluntary agreement with the owner of the patent, method, or process for a license under which the applicant for such abbreviated new drug application may use an aspect of the elements to assure safe use, if required under subsection (f) for the applicable listed drug, that is claimed by a patent that has not expired or is a method or process that as a trade secret is entitled to protection.”

Subsec. (i)(3). Pub. L. 116–94, § 610(f)(3), added par. (3).

Subsec. (l). Pub. L. 116–94, § 610(d), added subsec. (l).

Subsec. (m). Pub. L. 116–94, § 610(f)(4), added subsec. (m).

2018—Subsec. (b)(1)(E). Pub. L. 115–271, § 3041(a), substituted “of the drug, which may include reduced effectiveness under the conditions of use prescribed in the labeling of such drug, but which may not include reduced effectiveness that is in accordance with such labeling” for “of the drug”.

Subsec. (e)(4). Pub. L. 115–271, § 3032(a), added par. (4).

Subsec. (f)(2)(C)(iii). Pub. L. 115–271, § 3032(b), added cl. (iii).

Subsec. (i)(1)(B), (C). Pub. L. 115–271, § 3032(c)(1), added subpar. (B) and redesignated former subpar. (B) as (C).

Subsec. (i)(2)(B), (C). Pub. L. 115–271, § 3032(c)(2), added subpar. (B) and redesignated former subpar. (B) as (C).

2017—Subsec. (e)(3)(B). Pub. L. 115–52, § 606(1), struck out “; or” at end.

Subsec. (e)(3)(D). Pub. L. 115–52, § 606(2), (3), added subpar. (D).

2016—Subsec. (f)(5). Pub. L. 114–255, § 3075(c)(1), inserted “or other advisory committee” after “(or successor committee)” in introductory provisions.

Subsec. (f)(5)(B). Pub. L. 114–255, § 3075(c)(2), substituted “periodically” for “at least annually,” in introductory provisions.

Subsec. (h)(2)(A)(iii). Pub. L. 114–255, § 3101(a)(2)(C)(i), substituted, in heading, “labeling” for “label” and in text, “approved safety labeling changes” for “approved safety label changes”, “responsible person” for “sponsor”, and “a safety labeling change” for “a safety label change”.

Subsec. (h)(8). Pub. L. 114–255, § 3101(a)(2)(C)(ii), struck out period after “(7)”.

2013—Subsec. (f)(7). Pub. L. 113–5, § 302(c)(1), struck out par. (7) which related to waiver of subsec. (f) requirements in public health emergencies.

Subsec. (k). Pub. L. 113–5, § 302(c)(2), added subsec. (k).

2012—Subsec. (g)(1). Pub. L. 112–144, § 1132(a)(1), struck out “, and propose a modification to,” after “an assessment of”.

Subsec. (g)(2). Pub. L. 112–144, § 1132(a)(2)(A), in introductory provisions, struck out “, subject to paragraph (5),” after “shall” and “, and may propose a modification to,” after “an assessment of”.

Subsec. (g)(2)(C). Pub. L. 112–144, § 1132(a)(2)(B), substituted “an assessment is needed to evaluate whether the approved strategy should be modified to—” and cls. (i) and (ii) for “new safety or effectiveness information indicates that—

“(i) an element under subsection (d) or (e) should be modified or included in the strategy; or

“(ii) an element under subsection (f) should be modified or included in the strategy; or”.

Subsec. (g)(2)(D). Pub. L. 112–144, § 1132(a)(2)(C), struck out subpar. (D) which read as follows: “within 15 days when ordered by the Secretary, in consultation with the offices described in subsection (c)(2), if the Secretary determines that there may be a cause for action by the Secretary under section 355(e) of this title.”

Subsec. (g)(3). Pub. L. 112–144, § 1132(a)(3), substituted “for a drug shall include, with respect to each goal included in the strategy, an assessment of the extent to which the approved strategy, including each element of the strategy, is meeting the goal or whether 1 or more such goals or such elements should be modified.” for “for a drug shall include—” and struck out subpars. (A) to (C) which related to assessment of elements to assure safe use, postapproval studies, and postapproval clinical trials.

Subsec. (g)(4). Pub. L. 112–144, § 1132(a)(4), amended par. (4) generally. Prior to amendment, text read as follows: “A modification (whether an enhancement or a reduction) to the approved risk evaluation and mitigation strategy for a drug may include the addition or modification of any element under subsection (d) or the addition, modification, or removal of any element under subsection (e) or (f), such as—

“(A) modifying the timetable for assessments of the strategy as provided in subsection (d)(3), including to eliminate assessments; or

“(B) adding, modifying, or removing an element to assure safe use under subsection (f).”

Subsec. (h). Pub. L. 112–144, § 1132(b)(1), inserted “and modifications” after “review of assessments” in heading.

Subsec. (h)(1). Pub. L. 112–144, § 1132(b)(2), inserted “and proposed modification to” after “under subsection (a) and each assessment of” and “, and, if necessary, promptly initiate discussions with the responsible person about such proposed strategy, assessment, or modification” after “subsection (g)”.

Subsec. (h)(2). Pub. L. 112–144, § 1132(b)(3), (4), redesignated par. (3) as (2) and struck out former par. (2). Prior to amendment, text of par. (2) read as follows: “The Secretary, in consultation with the offices described in subsection (c)(2), shall initiate discussions with the responsible person for purposes of this subsection to determine a strategy not later than 60 days after any such assessment is submitted or, in the case of an assessment submitted under subsection (g)(2)(D), not later than 30 days after such assessment is submitted.”

Subsec. (h)(2)(A). Pub. L. 112–144, § 1132(b)(5)(A), amended subpar. (A) generally. Prior to amendment, subpar. (A) related to Secretary’s description of any required risk evaluation and mitigation strategy for a drug as part of the action letter on the application or in an order.

Subsec. (h)(2)(C). Pub. L. 112–144, § 1132(b)(5)(B), amended subpar. (C) generally. Prior to amendment, text read as follows: “Any action letter described in subparagraph (A)(i) or order described in subparagraph (A)(ii) shall be made publicly available.”

Subsec. (h)(3), (4). Pub. L. 112–144, § 1132(b)(4), redesignated pars. (4) and (5) as (3) and (4), respectively. Former par. (3) redesignated (2).

Subsec. (h)(4)(A)(i). Pub. L. 112–144, § 1132(b)(6)(A), substituted “The responsible” for “Not earlier than 15 days, and not later than 35 days, after discussions under paragraph (2) have begun, the responsible” and inserted “, after the sponsor is required to make a submission under subsection (a)(2) or (g),” before “request in writing”.

Subsec. (h)(4)(I). Pub. L. 112–144, § 1132(b)(6)(B), substituted “if the Secretary has complied with the timing requirements of scheduling review by the Drug Safety Oversight Board, providing a written recommendation, and issuing an action letter under subparagraphs (B), (F), and (G), respectively.” for “if the Secretary—” and struck out cls. (i) and (ii) which read as follows:

“(i) has initiated the discussions described under paragraph (2) not less than 60 days before such action deadline; and

“(ii) has complied with the timing requirements of scheduling review by the Drug Safety Oversight Board, providing a written recommendation, and issuing an action letter under subparagraphs (B), (F), and (G), respectively.”

Subsec. (h)(5). Pub. L. 112–144, § 1132(b)(4), (7), redesignated par. (6) as (5) and substituted “subparagraph (B) or (C)” for “any of subparagraphs (B) through (D)” in subpar. (A) and “paragraph (3) or (4)” for “paragraph (4) or (5)” in subpar. (C). Former par. (5) redesignated (4).

Subsec. (h)(6), (7). Pub. L. 112–144, § 1132(b)(4), redesignated pars. (7) and (8) as (6) and (7), respectively. Former par. (6) redesignated (5).

Subsec. (h)(8), (9). Pub. L. 112–144, § 1132(b)(4), (8), redesignated par. (9) as (8) and substituted “paragraphs (6) and (7).” for “paragraphs (7) and (8)”. Former par. (8) redesignated (7).

### Statutory Notes and Related Subsidiaries

### Effective Date

Section effective 180 days after Sept. 27, 2007, see section 909 of Pub. L. 110–85, set out as an Effective Date of 2007 Amendment note under section 331 of this title.

### Evidence-Based Opioid Analgesic Prescribing Guidelines and Report

Pub. L. 115–271, title III, § 3002, Oct. 24, 2018, 132 Stat. 3934, provided that: Guidelines.—The Commissioner of Food and Drugs shall develop evidence-based opioid analgesic prescribing guidelines for the indication-specific treatment of acute pain only for the relevant therapeutic areas where such guidelines do not exist. Public Input.—In developing the guidelines under subsection (a), the Commissioner of Food and Drugs shall— consult with stakeholders, which may include conducting a public meeting of medical professional societies (including any State-based societies), health care providers, State medical boards, medical specialties including pain medicine specialty societies, patient groups, pharmacists, academic or medical research entities, and other entities with experience in health care, as appropriate; collaborate with the Director of the Centers for Disease Control and Prevention, as applicable and appropriate, and other Federal agencies with relevant expertise as appropriate; and provide for a notice and comment period consistent with section 701(h) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 371(h)) for the submission of comments by the public. Report.—Not later than 1 year after the date of enactment of this Act [Oct. 24, 2018], or, if earlier, at the time the guidelines under subsection (a) are finalized, the Commissioner of Food and Drugs shall submit to the Committee on Energy and Commerce of the House of Representatives and the Committee on Health, Education, Labor, and Pensions of the Senate, and post on the public website of the Food and Drug Administration, a report on how the Food and Drug Administration will utilize the guidelines under subsection (a) to protect the public health and a description of the public health need with respect to each such indication-specific treatment guideline. Updates.—The Commissioner of Food and Drugs shall periodically— update the guidelines under subsection (a), informed by public input described in subsection (b); and submit to the committees specified in subsection (c) and post on the public website of the Food and Drug Administration an updated report under such subsection. Statement To Accompany Guidelines and Recommendations.—The Commissioner of Food and Drugs shall ensure that opioid analgesic prescribing guidelines and other recommendations developed under this section are accompanied by a clear statement that such guidelines or recommendations, as applicable— are intended to help inform clinical decisionmaking by prescribers and patients; and are not intended to be used for the purposes of restricting, limiting, delaying, or denying coverage for, or access to, a prescription issued for a legitimate medical purpose by an individual practitioner acting in the usual course of professional practice.”

### Prescriber Education

Pub. L. 114–198, title I, § 106(b), July 22, 2016, 130 Stat. 703, provided that: “Not later than 1 year after the date of the enactment of this Act [July 22, 2016], the Secretary [of Health and Human Services], acting through the Commissioner of Food and Drugs, as part of the Food and Drug Administration’s evaluation of the Extended-Release/Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy, and in consultation with relevant stakeholders, shall develop recommendations regarding education programs for prescribers of opioids pursuant to section 505–1 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355–1), including recommendations on— which prescribers should participate in such programs; and how often participation in such programs is necessary.”

### Guidance

Pub. L. 112–144, title XI, § 1132(c), July 9, 2012, 126 Stat. 1122, provided that: “Not later than 1 year after the date of enactment of this Act [July 9, 2012], the Secretary of Health and Human Services shall issue guidance that, for purposes of section 505–1(h)(2)(A) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355–1(h)(2)(A)), describes the types of modifications to approved risk evaluation and mitigation strategies that shall be considered to be minor modifications of such strategies.”