POSTMARKET STUDIES AND CLINICAL TRIALS REGARDING HUMAN DRUGS; RISK EVALUATION AND MITIGATION STRATEGIES.

SEC. 901. POSTMARKET STUDIES AND CLINICAL TRIALS REGARDING HUMAN DRUGS; RISK EVALUATION AND MITIGATION STRATEGIES.(a) In General.—Section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) is amended by adding at the end the following subsections:“(o) Postmarket Studies and Clinical Trials; Labeling.—“(1) In general.—A responsible person may not introduce or deliver for introduction into interstate commerce the new drug involved if the person is in violation of a requirement established under paragraph (3) or (4) with respect to the drug.“(2) Definitions.—For purposes of this subsection:“(A) Responsible person.—The term ‘responsible person’ means a person who—“(i) has submitted to the Secretary a covered application that is pending; or121 STAT. 923“(ii) is the holder of an approved covered application.“(B) Covered application.—The term ‘covered application’ means—“(i) an application under subsection (b) for a drug that is subject to section 503(b); and“(ii) an application under section 351 of the Public Health Service Act.“(C) New safety information; serious risk.—The terms ‘new safety information’, ‘serious risk’, and ‘signal of a serious risk’ have the meanings given such terms in section 505–1(b).“(3) Studies and clinical trials.—“(A) In general.—For any or all of the purposes specified in subparagraph (B), the Secretary may, subject to subparagraph (D), require a responsible person for a drug to conduct a postapproval study or studies of the drug, or a postapproval clinical trial or trials of the drug, on the basis of scientific data deemed appropriate by the Secretary, including information regarding chemically-related or pharmacologically-related drugs.“(B) Purposes of study or clinical trial.—The purposes referred to in this subparagraph with respect to a postapproval study or postapproval clinical trial are the following:“(i) To assess a known serious risk related to the use of the drug involved.“(ii) To assess signals of serious risk related to the use of the drug.“(iii) To identify an unexpected serious risk when available data indicates the potential for a serious risk.“(C) Establishment of requirement after approval of covered application.—The Secretary may require a postapproval study or studies or postapproval clinical trial or trials for a drug for which an approved covered application is in effect as of the date on which the Secretary seeks to establish such requirement only if the Secretary becomes aware of new safety information.“(D) Determination by secretary.—“(i) Postapproval studies.—The Secretary may not require the responsible person to conduct a study under this paragraph, unless the Secretary makes a determination that the reports under subsection (k)(1) and the active postmarket risk identification and analysis system as available under subsection (k)(3) will not be sufficient to meet the purposes set forth in subparagraph (B).“(ii) Postapproval clinical trials.—The Secretary may not require the responsible person to conduct a clinical trial under this paragraph, unless the Secretary makes a determination that a postapproval study or studies will not be sufficient to meet the purposes set forth in subparagraph (B).“(E) Notification; timetables; periodic reports.—“(i) Notification.—The Secretary shall notify the responsible person regarding a requirement under this 121 STAT. 924 paragraph to conduct a postapproval study or clinical trial by the target dates for communication of feedback from the review team to the responsible person regarding proposed labeling and postmarketing study commitments as set forth in the letters described in section 101(c) of the Food and Drug Administration Amendments Act of 2007.“(ii) Timetable; periodic reports.—For each study or clinical trial required to be conducted under this paragraph, the Secretary shall require that the responsible person submit a timetable for completion of the study or clinical trial. With respect to each study required to be conducted under this paragraph or otherwise undertaken by the responsible person to investigate a safety issue, the Secretary shall require the responsible person to periodically report to the Secretary on the status of such study including whether any difficulties in completing the study have been encountered. With respect to each clinical trial required to be conducted under this paragraph or otherwise undertaken by the responsible person to investigate a safety issue, the Secretary shall require the responsible person to periodically report to the Secretary on the status of such clinical trial including whether enrollment has begun, the number of participants enrolled, the expected completion date, whether any difficulties completing the clinical trial have been encountered, and registration information with respect to the requirements under section 402(j) of the Public Health Service Act. If the responsible person fails to comply with such timetable or violates any other requirement of this subparagraph, the responsible person shall be considered in violation of this subsection, unless the responsible person demonstrates good cause for such noncompliance or such other violation. The Secretary shall determine what constitutes good cause under the preceding sentence.“(F) Dispute resolution.—The responsible person may appeal a requirement to conduct a study or clinical trial under this paragraph using dispute resolution procedures established by the Secretary in regulation and guidance.“(4) Safety labeling changes requested by secretary.—“(A) New safety information.—If the Secretary becomes aware of new safety information that the Secretary believes should be included in the labeling of the drug, the Secretary shall promptly notify the responsible person or, if the same drug approved under section 505(b) is not currently marketed, the holder of an approved application under 505(j).“(B) Response to notification.—Following notification pursuant to subparagraph (A), the responsible person or the holder of the approved application under section 505(j) shall within 30 days—“(i) submit a supplement proposing changes to the approved labeling to reflect the new safety information, 121 STAT. 925 including changes to boxed warnings, contraindications, warnings, precautions, or adverse reactions; or“(ii) notify the Secretary that the responsible person or the holder of the approved application under section 505(j) does not believe a labeling change is warranted and submit a statement detailing the reasons why such a change is not warranted.“(C) Review.—Upon receipt of such supplement, the Secretary shall promptly review and act upon such supplement. If the Secretary disagrees with the proposed changes in the supplement or with the statement setting forth the reasons why no labeling change is necessary, the Secretary shall initiate discussions to reach agreement on whether the labeling for the drug should be modified to reflect the new safety information, and if so, the contents of such labeling changes.“(D) Discussions.—Such discussions shall not extend for more than 30 days after the response to the notification under subparagraph (B), unless the Secretary determines an extension of such discussion period is warranted.“(E) Order.—Within 15 days of the conclusion of the discussions under subparagraph (D), the Secretary may issue an order directing the responsible person or the holder of the approved application under section 505(j) to make such a labeling change as the Secretary deems appropriate to address the new safety information. Within 15 days of such an order, the responsible person or the holder of the approved application under section 505(j) shall submit a supplement containing the labeling change.“(F) Dispute resolution.—Within 5 days of receiving an order under subparagraph (E), the responsible person or the holder of the approved application under section 505(j) may appeal using dispute resolution procedures established by the Secretary in regulation and guidance.“(G) Violation.—If the responsible person or the holder of the approved application under section 505(j) has not submitted a supplement within 15 days of the date of such order under subparagraph (E), and there is no appeal or dispute resolution proceeding pending, the responsible person or holder shall be considered to be in violation of this subsection. If at the conclusion of any dispute resolution procedures the Secretary determines that a supplement must be submitted and such a supplement is not submitted within 15 days of the date of that determination, the responsible person or holder shall be in violation of this subsection.“(H) Public health threat.—Notwithstanding subparagraphs (A) through (F), if the Secretary concludes that such a labeling change is necessary to protect the public health, the Secretary may accelerate the timelines in such subparagraphs.“(I) Rule of construction.—This paragraph shall not be construed to affect the responsibility of the responsible person or the holder of the approved application under section 505(j) to maintain its label in accordance with existing requirements, including subpart B of part 201 121 STAT. 926 and sections 314.70 and 601.12 of title 21, Code of Federal Regulations (or any successor regulations).“(5) Non-delegation.—Determinations by the Secretary under this subsection for a drug shall be made by individuals at or above the level of individuals empowered to approve a drug (such as division directors within the Center for Drug Evaluation and Research).“(p) Risk Evaluation and Mitigation Strategy.—“(1) In general.—A person may not introduce or deliver for introduction into interstate commerce a new drug if—“(A)(i) the application for such drug is approved under subsection (b) or (j) and is subject to section 503(b); or“(ii) the application for such drug is approved under section 351 of the Public Health Service Act; and“(B) a risk evaluation and mitigation strategy is required under section 505–1 with respect to the drug and the person fails to maintain compliance with the requirements of the approved strategy or with other requirements under section 505–1, including requirements regarding assessments of approved strategies.“(2) Certain postmarket studies.—The failure to conduct a postmarket study under section 506, subpart H of part 314, or subpart E of part 601 of title 21, Code of Federal Regulations (or any successor regulations), is deemed to be a violation of paragraph (1).”.(b) Requirements Regarding Strategies.—Chapter V of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351 et seq.) is amended by inserting after section 505 the following section:“SEC. 505–1. RISK EVALUATION AND MITIGATION STRATEGIES.“(a) Submission of Proposed Strategy.—“(1) Initial approval.—If 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.“(C) The expected benefit of the drug with respect to such disease or condition.“(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.—121 STAT. 927 “(A) In general.—If the Secretary has approved a covered application (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 under paragraph (1), the Secretary, in consultation with the offices described in paragraph (1), may subsequently require such a strategy for the drug involved (including when acting on a supplemental application seeking approval of a new indication for use of the drug) if the Secretary becomes aware of new safety information and makes a determination that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks of the drug.“(B) Submission of proposed strategy.—Not later than 120 days after the Secretary notifies the holder of an approved covered application that the Secretary has made a determination under subparagraph (A) with respect to the drug involved, or within such other reasonable time as the Secretary requires to protect the public health, the holder shall submit to the Secretary a proposed risk evaluation and mitigation strategy.“(3) Abbreviated new drug applications.—The applicability of this section to an application under section 505(j) is subject to subsection (i).“(4) Non-delegation.—Determinations by the Secretary under this subsection for a drug shall be made by individuals at or above the level of individuals empowered to approve a drug (such as division directors within the Center for Drug 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 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;“(C) an adverse event occurring from abuse of the drug;“(D) an adverse event occurring from withdrawal of the drug; and“(E) any failure of expected pharmacological action of the drug.“(2) Covered application.—The term ‘covered application’ means an application referred to in section 505(p)(1)(A).“(3) New safety information.—The 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 505(o)(3)), or peer-reviewed biomedical literature; data derived from the postmarket risk identification and analysis system under section 505(k); 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 121 STAT. 928 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 experience.—The 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.—The term ‘serious risk’ means a risk of a serious adverse drug experience.“(6) Signal of a serious risk.—The 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;“(C) a postapproval study, including a study under section 505(o)(3);“(D) peer-reviewed biomedical literature;“(E) data derived from the postmarket risk identification and analysis system under section 505(k)(4); or“(F) other scientific data deemed appropriate by the Secretary.“(7) Responsible person.—The term ‘responsible person’ means the person submitting a covered application or the holder of the approved such application.“(8) Unexpected serious risk.—The term ‘unexpected serious risk’ means a serious adverse drug experience that is not listed in the labeling of a drug, or that may be symptomatically and pathophysiologically related to an adverse drug experience identified in the labeling, but differs from such adverse drug experience because of greater severity, specificity, or prevalence.“(c) Contents.—A proposed risk evaluation and mitigation strategy under subsection (a) shall—“(1) include the timetable required under subsection (d); and121 STAT. 929“(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 Strategy.—For 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.—The Secretary, in consultation with the offices described in subsection (c)(2), may under such subsection require that the risk evaluation and mitigation strategy for a drug include 1 or more of the additional elements described in this subsection if the Secretary makes the determination required with respect to each element involved.“(2) Medication guide; patient package insert.—The 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 plan.—The 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); or“(C) disseminating information to health care providers through professional societies about any serious risks of the drug and any protocol to assure safe use.121 STAT. 930“(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, in consultation with the offices described in subsection (c)(2), may require that the risk evaluation and mitigation strategy for a drug include such elements as are necessary to assure safe use of the drug, because of its inherent toxicity or potential harmfulness, if the Secretary determines that—“(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 burden.—Such 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;“(C) considering such risk, not be unduly burdensome on patient access to the drug, considering in particular—“(i) patients with serious or life-threatening diseases or conditions; and“(ii) patients who have difficulty accessing health care (such as patients in rural or medically underserved areas); 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 use.—The 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);121 STAT. 931“(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);“(C) the drug be dispensed to patients only in certain health care settings, such as hospitals;“(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 system.—The 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 use.—The Secretary, through the Drug Safety and Risk Management Advisory Committee (or successor 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 the burden on the health care delivery system;“(B) at least annually, 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“(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 as appropriate.“(6) Additional mechanisms to assure access.—The mechanisms under section 561 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, to a drug that is subject to elements to assure safe use under this subsection. The Secretary shall promulgate regulations for how a physician may provide the drug under the mechanisms of section 561.121 STAT. 932“(7) Waiver in public health emergencies.—The Secretary may waive any requirement of this subsection during the period described in section 319(a) of the Public Health Service Act with respect to a qualified countermeasure described under section 319F–1(a)(2) of such Act, to which a requirement under this subsection has been applied, if the Secretary has—“(A) declared a public health emergency under such section 319; and“(B) determined that such waiver is required to mitigate the effects of, or reduce the severity of, such public health emergency.“(8) Limitation.—No holder of an approved covered application shall use any element to assure safe use required by the Secretary under this subsection to block or delay approval of an application under section 505(b)(2) or (j) or to prevent application of such element 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 the approval of a risk evaluation and mitigation strategy under subsection (a), the responsible person involved may, subject to paragraph (2), submit to the Secretary an assessment of, and propose a modification to, the approved strategy for the drug involved at any time.“(2) Required assessments.—A responsible person shall, subject to paragraph (5), submit an assessment of, and may propose a modification to, the approved risk evaluation and mitigation strategy for a drug—“(A) when submitting a supplemental application for a new indication for use under section 505(b) or under section 351 of the Public Health Service Act, unless the drug is not subject to section 503(b) 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 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“(D) 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 505(e).“(3) Requirements for assessments.—An assessment under paragraph (1) or (2) of an approved risk evaluation and mitigation strategy for a drug shall include—“(A) with respect to any goal under subsection (f), an assessment of the extent to which the elements to assure safe use are meeting the goal or whether the goal or such elements should be modified;121 STAT. 933“(B) with respect to any postapproval study required under section 505(o) or otherwise undertaken by the responsible person to investigate a safety issue, the status of such study, including whether any difficulties completing the study have been encountered; and“(C) with respect to any postapproval clinical trial required under section 505(o) or otherwise undertaken by the responsible party to investigate a safety issue, the status of such clinical trial, including whether enrollment has begun, the number of participants enrolled, the expected completion date, whether any difficulties completing the clinical trial have been encountered, and registration information with respect to requirements under subsections (i) and (j) of section 402 of the Public Health Service Act.“(4) Modification.—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).“(h) Review of Proposed Strategies; Review of Assessments of Approved Strategies.—“(1) In general.—The Secretary, in consultation with the offices described in subsection (c)(2), shall promptly review each proposed risk evaluation and mitigation strategy for a drug submitted under subsection (a) and each assessment of an approved risk evaluation and mitigation strategy for a drug submitted under subsection (g).“(2) Discussion.—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.“(3) Action.—“(A) In general.—Unless the dispute resolution process described under paragraph (4) or (5) applies, the Secretary, in consultation with the offices described in subsection (c)(2), shall describe any required risk evaluation and mitigation strategy for a drug, or any modification to any required strategy—“(i) as part of the action letter on the application, when a proposed strategy is submitted under subsection (a) or a modification to the strategy is proposed as part of an assessment of the strategy submitted under subsection (g)(1); or“(ii) in an order issued not later than 90 days after the date discussions of such modification begin under paragraph (2), when a modification to the strategy is proposed as part of an assessment of the 121 STAT. 934 strategy submitted under subsection (g)(1) or under any of subparagraphs (B) through (D) of subsection (g)(2).“(B) Inaction.—An approved risk evaluation and mitigation strategy shall remain in effect until the Secretary acts, if the Secretary fails to act as provided under subparagraph (A).“(C) Public availability.—Any action letter described in subparagraph (A)(i) or order described in subparagraph (A)(ii) shall be made publicly available.“(4) Dispute resolution at initial approval.—If a proposed risk evaluation and mitigation strategy is submitted under subsection (a)(1) in an application for initial approval of a drug and there is a dispute about the strategy, the responsible person shall use the major dispute resolution procedures as set forth in the letters described in section 101(c) of the Food and Drug Administration Amendments Act of 2007.“(5) Dispute resolution in all other cases.—“(A) Request for review.—“(i) In general.—Not earlier than 15 days, and not later than 35 days, after discussions under paragraph (2) have begun, the responsible person may request in writing that a dispute about the strategy be reviewed by the Drug Safety Oversight Board under subsection (j), except that the determination of the Secretary to require a risk evaluation and mitigation strategy 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.“(ii) Scheduling.—Upon receipt of a request under clause (i), the Secretary shall schedule the dispute involved for review under subparagraph (B) and, not later than 5 business days of 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 Safety Oversight Board.“(B) Scheduling review.—If 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).“(C) Agreement after discussion or administrative appeals.—“(i) Further discussion or administrative appeals.—A request for review under subparagraph (A) shall not preclude further discussions to reach agreement on the risk evaluation and mitigation strategy, and such a request shall not preclude the use of administrative appeals within the Food and Drug Administration to reach agreement on the strategy, including appeals as described in the letters 121 STAT. 935 described in section 101(c) of the Food and Drug Administration Amendments Act of 2007 for procedural or scientific matters involving the review of human drug applications and supplemental applications that cannot be resolved at the divisional level. At the time a review has been scheduled under subparagraph (B) and notice of such review has been posted, the responsible person shall either withdraw the request under subparagraph (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) , the Secretary (in consultation with the offices described in subsection (c)(2)) and the responsible person may reach an agreement on the risk evaluation and mitigation strategy through further discussion or administrative appeals, terminating the dispute resolution process, and the Secretary shall issue an action letter or order, as appropriate, that describes the strategy.“(D) Meeting of the board.—At 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.—The Secretary shall ensure that the proceedings of any such meeting are recorded, transcribed, and made public within 90 days of the meeting. The Secretary shall redact the transcript to protect any trade secrets and other information that is exempted from disclosure under section 552 of title 5, United States Code, or section 552a of title 5, United States Code.“(F) Recommendation of the board.—Not later than 5 days after any such meeting, the Drug Safety Oversight Board shall provide a written recommendation on resolving the dispute to the Secretary. Not later than 5 days after the Board provides such written recommendation to the Secretary, the Secretary 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), 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.—With respect to an assessment of an approved risk evaluation and mitigation strategy under subsection (g)(1) or under any of subparagraphs (B) through (D) of subsection (g)(2), the Secretary shall issue an order, which shall be made public, that resolves the dispute not later than 7 days after 121 STAT. 936 receiving the recommendation of the Drug Safety Oversight Board.“(H) Inaction.—An approved risk evaluation and mitigation strategy shall remain in effect until the Secretary acts, if the Secretary fails to act as provided for under subparagraph (G).“(I) Effect on action deadline.—With respect to a proposal or assessment referred to in paragraph (1), the Secretary shall be considered to have met the action deadline for the action letter on the application if the responsible person requests the dispute resolution process described in this paragraph and if the Secretary—“(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.“(J) Disqualification.—No individual who is an employee of the Food and Drug Administration and who reviews a drug or who participated in an administrative appeal under subparagraph (C)(i) with respect to such drug may serve on the Drug Safety Oversight Board at a meeting under subparagraph (D) to review a dispute about the risk evaluation and mitigation strategy for such drug.“(K) Additional expertise.—The Drug Safety Oversight Board may add members with relevant expertise from the Food and Drug Administration, including the Office of Pediatrics, the Office of Women’s Health, or the Office of Rare Diseases, or from other Federal public health or health care agencies, for a meeting under subparagraph (D) of the Drug Safety Oversight Board.“(6) Use of advisory committees.—The 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 any of subparagraphs (B) through (D) of subsection (g)(2);“(B) review the risk evaluation and mitigation strategy or strategies of a drug or group of drugs; or“(C) review a dispute under paragraph (4) or (5).“(7) Process for addressing drug class effects.—“(A) In general.—When a concern about a serious risk of a drug may be related to the pharmacological class of the drug, the Secretary, in consultation with the offices described in subsection (c)(2), may defer assessments of the approved risk evaluation and mitigation strategies for such drugs until the Secretary has convened 1 or more public meetings to consider possible responses to such concern.“(B) Notice.—If the Secretary defers an assessment under subparagraph (A), the Secretary shall—121 STAT. 937“(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.“(C) Public meetings.—Such public meetings may include—“(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); or“(iii) 1 or more workshops of scientific experts and other stakeholders.“(D) Action.—After 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.“(8) International coordination.—The Secretary, in consultation with the offices described in subsection (c)(2), may coordinate the timetable for submission of assessments under subsection (d), or a study or clinical trial under section 505(o)(3), with efforts to identify and assess the serious risks of such drug by the marketing authorities of other countries whose drug approval and risk management processes the Secretary deems comparable to the drug approval and risk management processes of the United States. If the Secretary takes action to coordinate such timetable, the Secretary shall give notice to the responsible person.“(9) Effect.—Use of the processes described in paragraphs (7) and (8) shall not be the sole source of delay of action on an application or a supplement to an application for a drug.“(i) Abbreviated New Drug Applications.—“(1) In general.—A drug that is the subject of an abbreviated new drug application under section 505(j) 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) 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 121 STAT. 938 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.“(2) Action by secretary.—For an applicable listed drug for which a drug is approved under section 505(j), the Secretary—“(A) shall undertake any communication plan to health care providers required under subsection (e)(3) for the applicable listed drug; and“(B) 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.“(j) Drug Safety Oversight Board.—“(1) In general.—There is established a Drug Safety Oversight Board.“(2) Composition; meetings.—The 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.” .121 STAT. 939(c) Regulation of Biological Products.—Section 351 of the Public Health Service Act (42 U.S.C. 262) is amended—(1) in subsection (a)(2), by adding at the end the following:“(D) Postmarket Studies and Clinical Trials; Labeling; Risk Evaluation and Mitigation Strategy.—A person that submits an application for a license under this paragraph is subject to sections 505(o), 505(p), and 505–1 of the Federal Food, Drug, and Cosmetic Act.”; and(2) in subsection (j), by inserting “, including the requirements under sections 505(o), 505(p), and 505–1 of such Act,” after “, and Cosmetic Act”.(d) Advertisements of Drugs.—The Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et seq.), as amended by section 801(b), is amended—(1) in section 301 (21 U.S.C. 331), by adding at the end the following:“(kk) The dissemination of a television advertisement without complying with section 503B.”; and(2) by inserting after section 503A the following:“SEC. 503B. PREREVIEW OF TELEVISION ADVERTISEMENTS.“(a) In General.—The Secretary may require the submission of any television advertisement for a drug (including any script, story board, rough, or a completed video production of the television advertisement) to the Secretary for review under this section not later than 45 days before dissemination of the television advertisement.“(b) Review.—In conducting a review of a television advertisement under this section, the Secretary may make recommendations with respect to information included in the label of the drug—“(1) on changes that are—“(A) necessary to protect the consumer good and well-being; or“(B) consistent with prescribing information for the product under review; and“(2) if appropriate and if information exists, on statements for inclusion in the advertisement to address the specific efficacy of the drug as it relates to specific population groups, including elderly populations, children, and racial and ethnic minorities.“(c) No Authority to Require Changes.—Except as provided by subsection (e), this section does not authorize the Secretary to make or direct changes in any material submitted pursuant to subsection (a).“(d) Elderly Populations, Children, Racially and Ethnically Diverse Communities.—In formulating recommendations under subsection (b), the Secretary shall take into consideration the impact of the advertised drug on elderly populations, children, and racially and ethnically diverse communities.“(e) Specific Disclosures.—“(1) Serious risk; safety protocol.—In conducting a review of a television advertisement under this section, if the Secretary determines that the advertisement would be false or misleading without a specific disclosure about a serious risk listed in the labeling of the drug involved, the Secretary may require inclusion of such disclosure in the advertisement.121 STAT. 940“(2) Date of approval.—In conducting a review of a television advertisement under this section, the Secretary may require the advertisement to include, for a period not to exceed 2 years from the date of the approval of the drug under section 505 or section 351 of the Public Health Service Act, a specific disclosure of such date of approval if the Secretary determines that the advertisement would otherwise be false or misleading.“(f) Rule of Construction.—Nothing in this section may be construed as having any effect on requirements under section 502(n) or on the authority of the Secretary under section 314.550, 314.640, 601.45, or 601.94 of title 21, Code of Federal Regulations (or successor regulations).” .(3) Direct-to-consumer advertisements.—(A) In general.—Section 502(n) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 352(n)) is amended by adding at the end the following: “In the case of an advertisement for a drug subject to section 503(b)(1) presented directly to consumers in television or radio format and stating the name of the drug and its conditions of use, the major statement relating to side effects and contraindications shall be presented in a clear, conspicuous, and neutral manner.”.(B) Regulations to determine clear, conspicuous, and neutral manner.—Not later than 30 months after the date of the enactment of the Food and Drug Administration Amendments Act of 2007, the Secretary of Health and Human Services shall by regulation establish standards for determining whether a major statement relating to side effects and contraindications of a drug, described in section 502(n) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 352(n)) (as amended by subparagraph (A)) is presented in the manner required under such section.(4) Civil penalties.—Section 303 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 333), as amended by section 801(b), is amended by adding at the end the following:“(g)(1) With respect to a person who is a holder of an approved application under section 505 for a drug subject to section 503(b) or under section 351 of the Public Health Service Act, any such person who disseminates or causes another party to disseminate a direct-to-consumer advertisement that is false or misleading shall be liable to the United States for a civil penalty in an amount not to exceed $250,000 for the first such violation in any 3-year period, and not to exceed $500,000 for each subsequent violation in any 3-year period. No other civil monetary penalties in this Act (including the civil penalty in section 303(f)(4)) shall apply to a violation regarding direct-to-consumer advertising. For purposes of this paragraph: (A) Repeated dissemination of the same or similar advertisement prior to the receipt of the written notice referred to in paragraph (2) for such advertisements shall be considered one violation. (B) On and after the date of the receipt of such a notice, all violations under this paragraph occurring in a single day shall be considered one violation. With respect to advertisements that appear in magazines or other publications that are published less frequently than daily, each issue date (whether weekly or monthly) shall be treated as a single day for the purpose of calculating the number of violations under this paragraph.121 STAT. 941“(2) A civil penalty under paragraph (1) shall be assessed by the Secretary by an order made on the record after providing written notice to the person to be assessed a civil penalty and an opportunity for a hearing in accordance with this paragraph and section 554 of title 5, United States Code. If upon receipt of the written notice, the person to be assessed a civil penalty objects and requests a hearing, then in the course of any investigation related to such hearing, the Secretary may issue subpoenas requiring the attendance and testimony of witnesses and the production of evidence that relates to the matter under investigation, including information pertaining to the factors described in paragraph (3).“(3) The Secretary, in determining the amount of the civil penalty under paragraph (1), shall take into account the nature, circumstances, extent, and gravity of the violation or violations, including the following factors:“(A) Whether the person submitted the advertisement or a similar advertisement for review under section 736A.“(B) Whether the person submitted the advertisement for review if required under section 503B.“(C) Whether, after submission of the advertisement as described in subparagraph (A) or (B), the person disseminated or caused another party to disseminate the advertisement before the end of the 45-day comment period.“(D) Whether the person incorporated any comments made by the Secretary with regard to the advertisement into the advertisement prior to its dissemination.“(E) Whether the person ceased distribution of the advertisement upon receipt of the written notice referred to in paragraph (2) for such advertisement.“(F) Whether the person had the advertisement reviewed by qualified medical, regulatory, and legal reviewers prior to its dissemination.“(G) Whether the violations were material.“(H) Whether the person who created the advertisement or caused the advertisement to be created acted in good faith.“(I) Whether the person who created the advertisement or caused the advertisement to be created has been assessed a civil penalty under this provision within the previous 1-year period.“(J) The scope and extent of any voluntary, subsequent remedial action by the person.“(K) Such other matters, as justice may require.“(4)(A) Subject to subparagraph (B), no person shall be required to pay a civil penalty under paragraph (1) if the person submitted the advertisement to the Secretary and disseminated or caused another party to disseminate such advertisement after incorporating each comment received from the Secretary.“(B) The Secretary may retract or modify any prior comments the Secretary has provided to an advertisement submitted to the Secretary based on new information or changed circumstances, so long as the Secretary provides written notice to the person of the new views of the Secretary on the advertisement and provides a reasonable time for modification or correction of the advertisement prior to seeking any civil penalty under paragraph (1).“(5) The Secretary may compromise, modify, or remit, with or without conditions, any civil penalty which may be assessed 121 STAT. 942 under paragraph (1). The amount of such penalty, when finally determined, or the amount charged upon in compromise, may be deducted from any sums owed by the United States to the person charged.“(6) Any person who requested, in accordance with paragraph (2), a hearing with respect to the assessment of a civil penalty and who is aggrieved by an order assessing a civil penalty, may file a petition for de novo judicial review of such order with the United States Court of Appeals for the District of Columbia Circuit or for any other circuit in which such person resides or transacts business. Such a petition may only be filed within the 60-day period beginning on the date the order making such assessments was issued.“(7) If any person fails to pay an assessment of a civil penalty under paragraph (1)—“(A) after the order making the assessment becomes final, and if such person does not file a petition for judicial review of the order in accordance with paragraph (6), or“(B) after a court in an action brought under paragraph (6) has entered a final judgment in favor of the Secretary,the Attorney General of the United States shall recover the amount assessed (plus interest at currently prevailing rates from the date of the expiration of the 60-day period referred to in paragraph (6) or the date of such final judgment, as the case may be) in an action brought in any appropriate district court of the United States. In such an action, the validity, amount, and appropriateness of such penalty shall not be subject to review.”.(5) Report on direct-to-consumer advertising.—Not later than 24 months after the date of the enactment of this Act, the Secretary of Health and Human Services shall report to the Congress on direct-to-consumer advertising and its ability to communicate to subsets of the general population, including elderly populations, children, and racial and ethnic minority communities. The Secretary shall utilize the Advisory Committee on Risk Communication established under this Act to advise the Secretary with respect to such report. The Advisory Committee shall study direct-to-consumer advertising as it relates to increased access to health information and decreased health disparities for these populations. The report required by this paragraph shall recommend effective ways to present and disseminate information to these populations. Such report shall also make recommendations regarding impediments to the participation of elderly populations, children, racially and ethnically diverse communities, and medically underserved populations in clinical drug trials and shall recommend best practice approaches for increasing the inclusion of such subsets of the general population. The Secretary of Health and Human Services shall submit the report under this paragraph to the Committee on Health, Education, Labor, and Pensions of the Senate and the Committee on Energy and Commerce of the House of Representatives.(6) Rulemaking.—Section 502(n) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 352(n)) is amended by striking “the procedure specified in section 701(e) of this Act” and inserting “section 701(a)”.(e) Rule of Construction Regarding Pediatric Studies.—This title and the amendments made by this title may not be 121 STAT. 943 construed as affecting the authority of the Secretary of Health and Human Services to request pediatric studies under section 505A of the Federal Food, Drug, and Cosmetic Act or to require such studies under section 505B of such Act.