21 USC 355 - Risk evaluation and mitigation strategies

View all text of Part A [§ 351 - § 360n-2]

§ 355–1. Risk evaluation and mitigation strategies

(a) Submission of proposed strategy

(1) Initial approvalIf the Secretary, in consultation with the office responsible for reviewing the drug and the office responsible for postapproval safety with respect to the drug, determines that a risk evaluation and mitigation strategy is necessary to ensure that the benefits of the drug outweigh the risks of the drug, and informs the person who submits such application of such determination, then such person shall submit to the Secretary as part of such application a proposed risk evaluation and mitigation strategy. In making such a determination, the Secretary shall consider the following factors:

(A) The estimated size of the population likely to use the drug involved.

(B) The seriousness of the disease or condition that is to be treated with the drug.

(D) The expected or actual duration of treatment with the drug.

(E) The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug.

(F) Whether the drug is a new molecular entity.

(2) Postapproval requirement

(A) In general

(B) Submission of proposed strategy

(3) Abbreviated new drug applications

(4) Non-delegation

(b) DefinitionsFor purposes of this section:

(1) Adverse drug experienceThe term “adverse drug experience” means any adverse event associated with the use of a drug in humans, whether or not considered drug related, including—

(A) an adverse event occurring in the course of the use of the drug in professional practice;

(B) an adverse event occurring from an overdose of the drug, whether accidental or intentional;

(D) an adverse event occurring from withdrawal of the drug; and

(E) any failure of expected pharmacological action 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.

(2) Covered application

(3) New safety informationThe term “new safety information”, with respect to a drug, means information derived from a clinical trial, an adverse event report, a postapproval study (including a study under section 355(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; or other scientific data deemed appropriate by the Secretary about—

(A) a serious risk or an unexpected serious risk associated with use of the drug that the Secretary has become aware of (that may be based on a new analysis of existing information) since the drug was approved, since the risk evaluation and mitigation strategy was required, or since the last assessment of the approved risk evaluation and mitigation strategy for the drug; or

(B) the effectiveness of the approved risk evaluation and mitigation strategy for the drug obtained since the last assessment of such strategy.

(4) Serious adverse drug experienceThe term “serious adverse drug experience” is an adverse drug experience that—

(A) results in—

(i) death;

(ii) an adverse drug experience that places the patient at immediate risk of death from the adverse drug experience as it occurred (not including an adverse drug experience 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).

(5) Serious risk

(6) Signal of a serious riskThe term “signal of a serious risk” means information related to a serious adverse drug experience associated with use of a drug and derived from—

(A) a clinical trial;

(B) adverse event reports;

(D) peer-reviewed biomedical literature;

(E) data derived from the postmarket risk identification and analysis system under section 355(k)(4) of this title; or

(F) other scientific data deemed appropriate by the Secretary.

(7) Responsible person

(8) Unexpected serious risk

(1) include the timetable required under subsection (d); and

(2) to the extent required by the Secretary, in consultation with the office responsible for reviewing the drug and the office responsible for postapproval safety with respect to the drug, include additional elements described in subsections (e) and (f).

(d) Minimal strategyFor purposes of subsection (c)(1), the risk evaluation and mitigation strategy for a drug shall require a timetable for submission of assessments of the strategy that—

(1) includes an assessment, by the date that is 18 months after the strategy is initially approved;

(2) includes an assessment by the date that is 3 years after the strategy is initially approved;

(3) includes an assessment in the seventh year after the strategy is so approved; and

(4) subject to paragraphs (1), (2), and (3)—

(A) is at a frequency specified in the strategy;

(B) is increased or reduced in frequency as necessary as provided for in subsection (g)(4)(A); and

(C) is eliminated after the 3-year period described in paragraph (1) if the Secretary determines that serious risks of the drug have been adequately identified and assessed and are being adequately managed.

(e) Additional potential elements of strategy

(1) In general

(2) Medication Guide; patient package insertThe risk evaluation and mitigation strategy for a drug may require that, as applicable, the responsible person develop for distribution to each patient when the drug is dispensed—

(A) a Medication Guide, as provided for under part 208 of title 21, Code of Federal Regulations (or any successor regulations); and

(B) a patient package insert, if the Secretary determines that such insert may help mitigate a serious risk of the drug.

(3) Communication planThe risk evaluation and mitigation strategy for a drug may require that the responsible person conduct a communication plan to health care providers, if, with respect to such drug, the Secretary determines that such plan may support implementation of an element of the strategy (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 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

1 So in original. Probably should be followed by a semicolon.

(C) disseminating information to health care providers through professional societies about any serious risks of the drug and any protocol to assure safe use; or

(D) disseminating information to health care providers about drug 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 events associated with use of the drug.

(4) Packaging and disposalThe Secretary may require a risk evaluation mitigation strategy for a drug for which there is a serious risk of an adverse drug experience described in subparagraph (B) or (C) of subsection (b)(1), taking into consideration the factors described in subparagraphs (C) and (D) of subsection (f)(2) and in consultation with other relevant Federal agencies with authorities over drug disposal packaging, which may include requiring that—

(A) the drug 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 determines may mitigate such serious risk; or

(B) the drug be dispensed to certain patients with a safe disposal packaging or safe disposal system if the Secretary determines that such safe disposal packaging or system may mitigate such serious 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

(A) the drug, which has been shown to be effective, but is associated with a serious adverse drug experience, can be approved only if, or would be withdrawn unless, such elements are required as part of such strategy to mitigate a specific serious risk listed in the labeling of the drug; and

(B) for a drug initially approved without elements to assure safe use, other elements under subsections (c), (d), and (e) are not sufficient to mitigate such serious risk.

(2) Assuring access and minimizing burdenSuch elements to assure safe use under paragraph (1) shall—

(A) be commensurate with the specific serious risk listed in the labeling of the drug;

(B) within 30 days of the date on which any element under paragraph (1) is imposed, be posted publicly by the Secretary with an explanation of how such elements will mitigate the observed safety risk;

(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 with similar, serious risks; and

(ii) be designed to be compatible with established distribution, procurement, and dispensing systems for drugs.

(3) Elements to assure safe useThe elements to assure safe use under paragraph (1) shall include 1 or more goals to mitigate a specific serious risk listed in the labeling of the drug and, to mitigate such risk, may require that—

(A) health care providers who prescribe the drug have particular training or experience, or are specially certified (the opportunity to obtain such training or certification with respect to the drug 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 at reasonable cost to the provider);

(B) pharmacies, practitioners, or health care settings that dispense the drug are specially certified (the opportunity to obtain such certification shall be available to any willing provider from a frontier area);

(D) the drug be dispensed to patients with evidence or other documentation of safe-use conditions, such as laboratory test results;

(E) each patient using the drug be subject to certain monitoring; or

(F) each patient using the drug be enrolled in a registry.

(4) Implementation systemThe elements to assure safe use under paragraph (1) that are described in subparagraphs (B), (C), and (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.

(5) Evaluation of elements to assure safe useThe Secretary, through the Drug Safety and Risk Management Advisory Committee (or successor committee) or other advisory committee of the Food and Drug 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 may be standardized so as not to be—

(i) unduly burdensome on patient access to the drug; and

(ii) to the extent practicable, minimize 2

2 So in original. Does not follow from introductory provisions.

the burden on the health care delivery system;

(B) periodically evaluate, for 1 or more drugs, the elements to assure safe use of such drug to assess whether the elements—

(i) assure safe use of the drug;

(ii) are not unduly burdensome on patient access to the drug; and

(iii) to the extent practicable, minimize the burden on the health care delivery system; and

(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 as appropriate.

(6) Additional mechanisms to assure access

(7) Repealed. Pub. L. 113–5, title III, § 302(c)(1), Mar. 13, 2013, 127 Stat. 185

(8) Limitation

(g) Assessment and modification of approved strategy

(1) Voluntary assessments

(2) Required assessmentsA responsible person shall submit an assessment of the approved risk evaluation and mitigation strategy for a drug—

(A) when submitting a supplemental application for a new indication for use under section 355(b) of this title or under section 262 of title 42, unless the drug is not subject to section 353(b) of this title and the risk evaluation and mitigation strategy for the drug includes only the timetable under subsection (d);

(B) when required by the strategy, as provided for in such timetable under subsection (d);

(C) within a time period to be determined by the Secretary, if the Secretary, in consultation with the offices described in subsection (c)(2), determines that an assessment is needed to evaluate whether the approved strategy should be modified to—

(i) ensure the benefits of the drug outweigh the risks of the drug; or

(ii) minimize the burden on the health care delivery system of complying with the strategy.

(3) Requirements for assessments

(4) Modification

(A) On initiative of responsible person

(B) On initiative of SecretaryAfter the approval of a risk evaluation and mitigation strategy by the Secretary, the Secretary may, at any time, require a responsible person to submit a proposed modification to the strategy within 120 days or within such reasonable time as the Secretary specifies, if the Secretary, in consultation with the offices described in subsection (c)(2), determines that 1 or more goals or elements should be added, modified, or removed from the approved strategy to—

(i) ensure the benefits of the drug outweigh the risks of the drug;

(ii) minimize the burden on the health care delivery system of complying with the strategy; or

(iii) accommodate different, comparable aspects of the elements to assure safe use for a drug that is the subject of an application under section 355(j) of this title, and the applicable listed drug.

(h) Review of proposed strategies; review of assessments and modifications of approved strategies

(1) In general

(2) Action

(A) In general

(i) Timeframe

(ii) Minor modifications

(iii) REMS modification due to safety labeling changes

(iv) Guidance

(B) Inaction

(3) Dispute resolution at initial approval

(4) Dispute resolution in all other cases

(A) Request for review

(i) In general

(ii) Scheduling

(B) Scheduling reviewIf a responsible person requests review under subparagraph (A), the Secretary—

(i) shall schedule the dispute for review at 1 of the next 2 regular meetings of the Drug Safety Oversight Board, whichever meeting date is more practicable; or

(ii) may convene a special meeting of the Drug Safety Oversight Board to review the matter more promptly, including to meet an action deadline on an application (including a supplemental application).

(i) Further discussion or administrative appeals

(ii) Agreement terminates dispute resolution

(D) Meeting of the BoardAt a meeting of the Drug Safety Oversight Board described in subparagraph (B), the Board shall—

(i) hear from both parties via written or oral presentation; and

(ii) review the dispute.

(E) Record of proceedings

(F) Recommendation of the Board

(G) Action by the Secretary

(i) Action letterWith respect to a proposal or assessment referred to in paragraph (1), the Secretary 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 Safety Oversight Board.

(ii) Order

(H) Inaction

(I) Effect on action deadline

(J) Disqualification

(K) Additional expertise

(5) Use of advisory committeesThe Secretary may convene a meeting of 1 or more advisory committees of the Food and Drug Administration to—

(A) review a concern about the safety of a drug or class of drugs, including before an assessment of the risk evaluation and mitigation strategy or strategies of such drug or drugs is required to be submitted under subparagraph (B) or (C) of subsection (g)(2);

(B) review the risk evaluation and mitigation strategy or strategies of a drug or group of drugs; or

(6) Process for addressing drug class effects

(A) In general

(B) NoticeIf the Secretary defers an assessment under subparagraph (A), the Secretary shall—

(i) give notice of the deferral to the holder of the approved covered application 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), including a description of the deferral.

(i) 1 or more meetings of the responsible person for such drugs;

(ii) 1 or more meetings of 1 or more advisory committees of the Food and Drug Administration, as provided for under paragraph (6); 4

4 See References in Text note below.

(iii) 1 or more workshops of scientific experts and other stakeholders.

(D) ActionAfter considering the discussions from any meetings under subparagraph (A), the Secretary may—

(i) announce in the Federal Register a planned regulatory action, including a modification to each risk evaluation and mitigation strategy, for drugs 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

(8) Effect

(i) Abbreviated new drug applications

(1) In generalA drug that is the subject of an abbreviated new drug application under section 355(j) of this title is subject to only the following elements of the risk evaluation and mitigation strategy required under subsection (a) for the applicable listed drug:

(A) A Medication Guide or patient package insert, if required under subsection (e) for the applicable listed drug.

(B) A packaging or disposal requirement, if required under subsection (e)(4) for the applicable listed drug.

(C)

(i) Elements to assure safe use, if required under subsection (f) for the listed drug, which, subject to clause (ii), for a drug that is the subject of an application under section 355(j) of this title may use—(I) a single, shared system with the listed drug under subsection (f); or(II) a different, comparable aspect of the elements to assure safe use under subsection (f).

(ii) The Secretary may require a drug that is the subject of an application under section 355(j) of this title and the listed drug to use a single, shared system under subsection (f), if the Secretary determines that no different, comparable aspect of the elements to assure safe use could satisfy the requirements of subsection (f).

(2) Action by SecretaryFor an applicable listed drug for which a drug is approved under section 355(j) of this title, the Secretary—

(A) shall undertake any communication plan to health care providers required under subsection (e)(3) for the applicable listed drug;

(B) shall permit packaging systems and safe disposal packaging or safe disposal systems that are different from those required for the applicable listed drug under subsection (e)(4); and

(C) shall inform the responsible person for the drug that is so approved if the risk evaluation and mitigation strategy for the applicable listed drug is modified.

(3) Shared REMS

(j) Drug Safety Oversight Board

(1) In general

(2) Composition; meetingsThe Drug Safety Oversight Board shall—

(A) be composed of scientists and health care practitioners appointed by the Secretary, each of whom is an employee of the Federal Government;

(B) include representatives from offices throughout the Food and Drug Administration, including the offices responsible for postapproval safety of drugs;

(C) include at least 1 representative each from the National Institutes of Health and the Department of Health and Human Services (other than the Food and Drug Administration);

(D) include such representatives as the Secretary 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 on the management of important drug safety issues.

(k) Waiver in public health emergenciesThe Secretary may waive any requirement of this section with respect to a qualified countermeasure (as defined in section 247d–6a(a)(2) of title 42) to which a requirement under this section has been applied, if the Secretary 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 has been made by the Secretary of Homeland Security, the Secretary of Defense, or the Secretary, respectively; or

(2) the identification of a material threat described in subparagraph (D) of section 360bbb–3(b)(1) of this title has been made pursuant to section 247d–6b of title 42.

(l) Provision of samples not a violation of strategy

(m) Separate REMS

(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.)