225 
‘‘(B) whether the responsible party has en-
gaged in a pattern or practice of noncompli-
ance; and 
‘‘(C) the extent to which the noncompli-
ance involved may have significantly misled 
health care providers or patients concerning the 
safety or effectiveness of the drug involved. 
‘‘(4) CIVIL PENALTIES.— 
‘‘(A) IN GENERAL.—A person is subject to 
a civil penalty in accordance with this para-
graph if the person commits a violation de-
scribed in paragraph (1) and fails to correct the 
violation by the end of the 30-day period de-
scribed in subparagraph (B). 
‘‘(B) NOTIFICATION.—If a person is in vio-
lation of paragraph (1), the Secretary shall no-
tify the person of such noncompliance and give 
the person a 30-day period to correct such vio-
lation before imposing a civil penalty under this 
paragraph. 
‘‘(C) AMOUNT OF PENALTY.—The amount 
of a civil penalty under this subsection shall be 
not more than a total of $15,000 for all viola-
tions adjudicated in a single proceeding in the 
case of an individual, and not more than
226 
$10,000 per day until the violation is corrected 
in the case of any other person, except that if 
the person is a nonprofit entity the penalty may 
not exceed a total of $15,000 for all violations 
adjudicated in a single proceeding. 
‘‘(D) PROCEDURES.—The provisions of 
paragraphs (4) through (6) of section 303(f) of 
the Federal Food, Drug, and Cosmetic Act 
apply to the imposition of a penalty under this 
subsection to the same extent and in the same 
manner as such provisions apply to a penalty 
imposed under such section 303(f). 
‘‘(g) AUTHORIZATION OF APPROPRIATIONS.—There 
are authorized to be appropriated to carry out this section 
$10,000,000 for each fiscal year.’’. 
(b) CONFORMING AMENDMENTS.— 
(1) INVESTIGATIONAL
NEW
DRUGS.—Section 
505(i) of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 355(i)) is amended— 
(A) in paragraph (1)— 
(i) in subparagraph (C), by striking 
‘‘and’’ after the semicolon; 
(ii) in subparagraph (D)— 
(I) by aligning the indentation of 
such subparagraph with the indenta-
227 
tion of subparagraphs (A), (B), and 
(C); and 
(II) by striking the period at the 
end and inserting ‘‘; and’’; and 
(iii) by adding at the end the fol-
lowing: 
‘‘(E) the submission to the Director of NIH of 
clinical trial information for the clinical investigation 
at issue required under section 492C of the Public 
Health Service Act for inclusion in the registry data-
base and the results database described in such sec-
tion.’’; 
(B) in paragraph (3)(B)— 
(i) in clause (i), by striking ‘‘or’’ after 
the semicolon; 
(ii) in clause (ii), by striking the pe-
riod at the end and inserting ‘‘; or’’; and 
(iii) by adding at the end the fol-
lowing: 
‘‘(iii) clinical trial information for the clinical 
investigation at issue was not submitted in compli-
ance with section 492C of the Public Health Service 
Act.’’; and 
(C) in paragraph (4), by adding at the end 
the following: ‘‘The Secretary shall update such
228 
regulations to require inclusion in the informed 
consent form a statement that clinical trial in-
formation for such clinical investigation will be 
submitted for inclusion in the registry database 
and results database, as applicable, described in 
section 492C of the Public Health Service 
Act.’’. 
(2) REFUSAL TO APPROVE NEW DRUG APPLICA-
TION.—Section 505(d) of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 355(d)) is amended— 
(A) in the first sentence, by inserting after 
‘‘in any particular;’’ the following: ‘‘or (8) the 
applicant failed to submit the clinical trial in-
formation for any applicable clinical trial as re-
quired by section 492C of the Public Health 
Service Act;’’; and 
(B) in the second sentence, by striking 
‘‘clauses (1) through (6)’’ and inserting ‘‘para-
graphs (1) through (8)’’. 
(3) INVESTIGATIONAL
NEW
DEVICES.—Sub-
paragraph (B) of section 520(g)(2) of the Federal 
Food, 
Drug, 
and 
Cosmetic 
Act 
(21 
U.S.C. 
360j(g)(2)) is amended— 
(A) by redesignating clause (iii) as clause 
(iv); and
229 
(B) by inserting after clause (ii) the fol-
lowing: 
‘‘(iii) A requirement that the person applying 
for an exemption for a device assure that such per-
son is in compliance with the requirements of section 
492C of the Public Health Service Act for the sub-
mission of clinical trial information for inclusion in 
the registry database and the results database de-
scribed in such section.’’. 
(4) REFUSAL
TO
CLEAR
NEW
DEVICE
PRE-
MARKET NOTIFICATION REPORT.—Subsection (k) of 
section 510 of the Federal Food, Drug, and Cos-
metic Act (21 U.S.C. 360) is amended— 
(A) in paragraph (1), by striking ‘‘and’’ at 
the end; and 
(B) in paragraph (2), by striking the pe-
riod at the end and inserting ‘‘, and’’; and 
(C) by adding at the end the following: 
‘‘(3) action taken by such person to comply 
with requirements under section 492C of the Public 
Health Service Act for the submission of clinical 
trial information for inclusion in the registry data-
base and the results database described in such sec-
tion.’’.
230 
(5) REFUSAL TO APPROVE NEW DEVICE APPLI-
CATION.—Paragraph (2) of section 515(d) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
360e(d)) is amended— 
(A) in subparagraph (D), by striking ‘‘or’’ 
at the end; 
(B) in subparagraph (E), by striking the 
period at the end and inserting ‘‘; or’’; and 
(C) by inserting after subparagraph (E) 
the following: 
‘‘(F) the applicant is in violation of the require-
ments under section 492C of the Public Health 
Service Act for the submission of clinical trial infor-
mation for inclusion in the registry database or the 
results database described in such section.’’. 
(c) GUIDANCE.—Not later than 180 days after the 
date of the enactment of this Act, the Commissioner of 
Food and Drugs, in consultation with the Director of the 
National Institutes of Health, shall issue guidance to clar-
ify which clinical trials are applicable clinical trials (as de-
fined in section 492C of the Public Health Service Act, 
as amended by this section) and required to be submitted 
for inclusion in the clinical trial registry database de-
scribed in such section. 
(d) PREEMPTION.—
231 
(1) IN GENERAL.—No State or political subdivi-
sion of a State may establish or continue in effect 
any requirement for the registration of clinical trials 
or any requirement for the inclusion of information 
relating to the results of clinical trials in a database. 
(2) RULE OF CONSTRUCTION.—The fact of sub-
mission of clinical trial information, if submitted in 
compliance with section 492C of the Public Health 
Service Act (as amended by this section), that re-
lates to a use of a drug or device not included in the 
official labeling of the approved drug or device shall 
not be construed by the Secretary or in any adminis-
trative or judicial proceeding, as evidence of a new 
intended use of the drug or device that is different 
from the intended use of the drug or device set forth 
in the official labeling of the drug or device. The 
availability of clinical trial information through the 
databases under subsections (b) and (c) of such sec-
tion 492C, if submitted in compliance with such sec-
tion 492C, shall not be considered as labeling, adul-
teration, or misbranding of the drug or device under 
the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 301 et seq.). 
(e) EFFECTIVE DATES.—
232 
(1) ESTABLISHMENT OF REGISTRY DATABASE 
AND RESULTS DATABASE.—Not later than 1 year 
after the date of the enactment of this Act, the Di-
rector of NIH shall establish the registry database 
and the results database of clinical trials of drugs 
and devices in accordance with section 492C of the 
Public Health Service Act (as amended by sub-
section (a)). 
(2) CLINICAL TRIALS INITIATED PRIOR TO OP-
ERATION OF REGISTRY DATABASE.—The responsible 
party (as defined in such section 492C) for an appli-
cable clinical trial (as defined in such section 492C) 
that is initiated after the date of the enactment of 
this Act and before the date such registry database 
is established under paragraph (1) of this sub-
section, shall submit required clinical trial informa-
tion not later than 120 days after the date such reg-
istry database is established. 
(3) CLINICAL TRIALS INITIATED AFTER OPER-
ATION
OF
REGISTRY
DATABASE.—The responsible 
party (as defined in such section 492C) for an appli-
cable clinical trial (as defined in such section 492C) 
that is initiated after the date such registry database 
is established under paragraph (1) of this subsection
233 
shall submit required clinical trial information in ac-
cordance with subsection (b) of such section 492C. 
(4) TRIALS
COMPLETED
BEFORE
OPERATION 
OF RESULTS DATABASE.— 
(A) IN GENERAL.—Subsection (c) of such 
section 492C shall take effect 90 days after the 
date the results database is established under 
paragraph (1) of this subsection with respect to 
any applicable clinical trial (as defined in such 
section 492C) that— 
(i) involves a drug to treat a serious 
or life-threatening condition; and 
(ii) is completed between the date of 
the enactment of this Act and such date of 
establishment under paragraph (1) of this 
subsection. 
(B) OTHER TRIALS.—Except as provided 
in subparagraph (A), subsection (c) of such sec-
tion 492C shall take effect 180 days after the 
date that the results database is established 
under paragraph (1) of this subsection with re-
spect to any applicable clinical trial that is com-
pleted between the date of the enactment of this 
Act and such date of establishment under para-
graph (1).
234 
(5) TRIALS
COMPLETED
AFTER
ESTABLISH-
MENT OF RESULTS DATABASE.—Subsection (c) of 
such section 492C shall apply to any clinical trial 
that is completed after the date that the results 
database is established under paragraph (1) of this 
subsection. 
(6) RETROACTIVITY OF DATABASE.— 
(A) VOLUNTARY SUBMISSIONS.—The Sec-
retary of Health and Human Services (referred 
to in this paragraph as the ‘‘Secretary’’) shall 
establish procedures and mechanisms to allow 
for the voluntary submission to the Secretary— 
(i) of clinical trial information for in-
clusion in the registry database (as defined 
in such section 492C) on applicable clinical 
trials (as defined in such section 492C) 
initiated before the date of the enactment 
of this Act; and 
(ii) of clinical trial information for in-
clusion in the results database (as defined 
in such section 492C) on applicable clinical 
trials (as defined in such section 492C) 
completed before the date of the enactment 
of this Act.
235 
(B) REQUIRED
SUBMISSIONS.—Notwith-
standing the preceding paragraphs of this sub-
section, in any case in which the Secretary de-
termines that submission of clinical trial infor-
mation for an applicable clinical trial (as de-
fined in such section 492C) described in clause 
(i) or (ii) of subparagraph (A) is in the interest 
of the public health— 
(i) the Secretary may require that 
such information be submitted to the Sec-
retary in accordance with such section 
492C; and 
(ii) failure to comply with such a re-
quirement shall be treated as a violation of 
the corresponding requirement of such sec-
tion 492C. 
(7) 
STATUS
OF
CLINICALTRIALS.GOV 
WEBSITE.— 
(A) IN GENERAL.—After receiving public 
comment and not later than 90 days after the 
date of the enactment of this Act, the Secretary 
shall publish in the Federal Register a notice 
determining the more efficient approach to es-
tablishing the registry database described in
236 
subsection (b) of such section 492C and wheth-
er such approach is— 
(i) that such registry database should 
expand and build upon the data bank de-
scribed in section 402(i) of the Public 
Health Service Act (as in effect on the day 
before the date of the enactment of this 
Act); or 
(ii) that such registry database should 
supplant the data bank described in such 
section 402(i) (as in effect on the day be-
fore the date of the enactment of this Act). 
(B) CLINICALTRIALS.GOV SUPPLANTED.— 
If the Secretary determines to apply the ap-
proach described under subparagraph (A)(ii), 
the Secretary shall maintain an archive of the 
data bank described in such section 402(i) (as 
in effect on the day before the date of the en-
actment of this Act) on the Internet website of 
the National Library of Medicine. 
SEC. 802. STUDY BY GOVERNMENT ACCOUNTABILITY OF-
FICE. 
(a) IN GENERAL.—The Comptroller General of the 
United States shall conduct a study to determine whether 
information on the trials registry and database is consid-
237 
ered promotional and to evaluate the implementation of 
this database. 
(b) REPORT.—Not later than one year after the date 
of the enactment of this Act, the Comptroller General shall 
complete the study under subsection (a) and submit to the 
Congress a report on the results of such study. 
TITLE IX—ENHANCED AUTHORI-
TIES 
REGARDING 
POSTMARKET 
SAFETY 
OF 
DRUGS 
SEC. 901. POSTMARKET STUDIES AND CLINICAL TRIALS RE-
GARDING 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 inter-
state 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 sub-
section:
238 
‘‘(A) RESPONSIBLE
PERSON.—The term 
‘responsible person’ means a person who— 
‘‘(i) has submitted to the Secretary a 
covered application that is pending; or 
‘‘(ii) is the holder of an approved cov-
ered 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’, ‘se-
rious 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 (C), re-
quire 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
239 
drug, on the basis of scientific information, in-
cluding information regarding chemically-re-
lated or pharmacologically-related drugs. 
‘‘(B) PURPOSES
OF
STUDY
OR
TRIAL.— 
The purposes referred to in this subparagraph 
with respect to a postapproval study or post-
approval 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 a serious risk. 
‘‘(C) ESTABLISHMENT
OF
REQUIREMENT 
AFTER APPROVAL OF COVERED APPLICATION.— 
The Secretary may require a postapproval study 
or studies or postapproval trial or trials for a 
drug for which an approved covered application 
is in effect as of the date on which the Sec-
retary seeks to establish such requirement only 
if the Secretary becomes aware of new safety 
information. For each study required to be con-
ducted under this subparagraph, the Secretary 
shall require that the applicant submit a time-
table for completion of the study and shall re-
quire the applicant to periodically report to the
240 
Secretary on the status of the study. Unless the 
applicant demonstrates good cause for failure to 
comply with such timeline, the applicant shall 
be in violation of this subsection. The Secretary 
shall determine what constitutes good cause 
under the preceding sentence. 
‘‘(4) SAFETY LABELING CHANGES REQUESTED 
BY SECRETARY.— 
‘‘(A) NEW
SAFETY
INFORMATION.—The 
Secretary shall promptly notify the responsible 
person if the Secretary becomes aware of new 
safety information that the Secretary believes 
should be included in the labeling of the drug. 
‘‘(B) RESPONSE TO NOTIFICATION.—Fol-
lowing notification pursuant to subparagraph 
(A), the responsible person shall within 30 
days— 
‘‘(i) submit a supplement proposing 
changes to the approved labeling to reflect 
the new safety information, including 
changes to boxed warnings, contraindica-
tions, warnings, precautions, or adverse re-
actions; or 
‘‘(ii) notify the Secretary that the re-
sponsible person does not believe a labeling
241 
change is warranted and submit a state-
ment detailing the reasons why such a 
change is not warranted. 
‘‘(C) REVIEW.—Upon receipt of such sup-
plement, the Secretary shall promptly review 
and act upon such supplement. If the Secretary 
disagrees with the proposed changes in the sup-
plement or with the statement setting forth the 
responsible person’s reasons why no labeling 
change is necessary, the Secretary shall initiate 
discussions with the responsible person to reach 
agreement on whether the labeling for the drug 
should be modified to reflect the new safety in-
formation, and if so, the contents of such label-
ing changes. 
‘‘(D) 
DISCUSSIONS.—Such 
discussions 
shall not extend for more than 30 days after 
the response to the notification under subpara-
graph (B), unless the Secretary determines an 
extension of such discussion period is war-
ranted. 
‘‘(E) ORDER.—Within 15 days of the con-
clusion of the discussions under subparagraph 
(D), the Secretary may issue an order directing 
the responsible person to make such a labeling
242 
change as the Secretary deems appropriate to 
address the new safety information. Within 15 
days of such an order, the responsible person 
shall submit a supplement containing the label-
ing change. 
‘‘(F) DISPUTE
RESOLUTION.—Within 5 
days of receiving an order under subparagraph 
(E), the responsible person may appeal using 
the Food and Drug Administration’s normal 
dispute resolution procedures established by the 
Secretary in regulation and guidance. 
‘‘(G) VIOLATION.—If the change required 
by an order under subparagraph (E) is not 
made by the date so specified, the responsible 
person shall be considered to be in violation of 
this section. 
‘‘(H) SERIOUS PUBLIC HEALTH THREAT.— 
Notwithstanding subparagraphs (A) through 
(F), if the Secretary concludes that failure to 
make such a labeling change is necessary to 
protect against a serious public health threat, 
the Secretary may accelerate the timelines in 
such subparagraphs. 
‘‘(I) RULE OF CONSTRUCTION.—This para-
graph shall not be construed to affect the re-
243 
sponsibility of the responsible person to main-
tain its label in accordance with existing re-
quirements, including subpart B and section 
314.70 of title 21, Code of Federal Regulations 
(or any successor regulations). 
‘‘(p) RISK EVALUATION AND MITIGATION STRAT-
EGY.— 
‘‘(1) IN GENERAL.—A person may not intro-
duce or deliver for introduction into interstate com-
merce a new drug if— 
‘‘(A)(i) the application for such drug is ap-
proved under subsection (b) or (j) and is sub-
ject to section 503(b); or 
‘‘(ii) the application for such drug is ap-
proved 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— 
‘‘(i) the person fails to maintain com-
pliance with the requirements of the ap-
proved strategy or with other requirements 
under section 505–1, including require-
ments regarding assessments of approved 
strategies; or
244 
‘‘(ii) in the case of a requirement for 
such a strategy that is first established 
after the applicable application referred to 
in subparagraph (A) was approved with re-
spect to the drug, the Secretary, after no-
tice and opportunity for a hearing, pub-
lishes in the Federal Register a statement 
that the person is not cooperating with the 
Secretary in developing such a strategy for 
the drug. 
‘‘(2) REQUIRED STATEMENT DURING APPROVAL 
PROCESS.—In the case of an application approved 
under subsection (b) or (j) for a new drug that is 
subject to section 503(b), or an application approved 
under section 351 of the Public Health Service Act, 
or a supplement to such an application that requires 
substantive data, the Secretary may not approve the 
application or supplement unless the person involved 
has complied with the following: 
‘‘(A) The person has submitted to the Sec-
retary a statement that provides the following 
information: 
‘‘(i) Whether the person believes that 
a risk evaluation and mitigation strategy 
should be required under section 505–1.
245 
‘‘(ii) Whether a postmarket study or 
clinical trial should be required under sub-
section (o)(3). 
‘‘(B) In making the statement under sub-
paragraph (A), the person took into account 
each of the following factors: 
‘‘(i) The estimated size of the popu-
lation likely to use the drug involved. 
‘‘(ii) The seriousness of the disease or 
condition that is to be treated with the 
drug. 
‘‘(iii) The expected benefit of the drug 
with respect to such disease or condition. 
‘‘(iv) The expected or actual duration 
of treatment with the drug. 
‘‘(v) The seriousness of any known or 
potential adverse events that may be re-
lated to the drug and the background inci-
dence of such events in the population like-
ly to use the drug. 
‘‘(3) CERTAIN
POSTMARKET
STUDIES.—The 
failure to conduct a postmarket study under subpart 
H of part 314 of title 21, Code of Federal Regula-
tions (or any successor regulation), is deemed to be 
a violation of paragraph (1).’’.
246 
(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 sec-
tion 505 the following section: 
‘‘SEC. 505–1. RISK EVALUATION AND MITIGATION STRATE-
GIES. 
‘‘(a) SUBMISSION OF PROPOSED STRATEGY.— 
‘‘(1) INITIAL APPROVAL.—A person who sub-
mits 
an 
application 
referred 
to 
in 
section 
505(p)(1)(A) (referred to in this section as a ‘cov-
ered application’) shall submit to the Secretary as 
part of the application a proposed risk evaluation 
and mitigation strategy if the Secretary determines 
such a strategy is necessary to ensure that the bene-
fits of the drug involved outweigh the risks of the 
drug. In making such a determination, the Secretary 
shall consider the statement submitted by the person 
under section 505(p)(2) with respect to the drug and 
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 con-
dition that is to be treated with the drug. 
‘‘(C) The expected benefit of the drug with 
respect to such disease or condition.
247 
‘‘(D) The expected or actual duration of 
treatment with the drug. 
‘‘(E) The seriousness of any known or po-
tential 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) The availability and safety of a drug 
or other treatment, if any, for such disease or 
condition to which the safety of the drug may 
be compared. 
‘‘(G) Whether the drug is a new molecular 
entity. 
‘‘(2) POSTAPPROVAL REQUIREMENT.— 
‘‘(A) IN GENERAL.—If the Secretary ap-
proves a covered application and does not when 
approving the application require a risk evalua-
tion and mitigation strategy under paragraph 
(1), the Secretary may subsequently require 
such a strategy for the drug involved if the Sec-
retary 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
STRAT-
EGY.—Not later than 120 days after the Sec-
248 
retary notifies the holder of an approved cov-
ered application that the Secretary has made a 
determination under subparagraph (A) with re-
spect to the drug involved, or within such other 
time as the Secretary requires to protect the 
public health, the holder shall submit to the 
Secretary a proposed risk evaluation and miti-
gation strategy. 
‘‘(3) APPROVAL
OF
NEW
INDICATION
FOR 
USE.—The applicability of paragraph (2) includes 
applicability to a drug for which an approved cov-
ered application was in effect on the day before the 
effective date of this section and for which, on or 
after such effective date, the holder of the approved 
application submits to the Secretary a supplemental 
application seeking approval of a new indication for 
use of the drug. 
‘‘(4) 
ABBREVIATED
NEW
DRUG
APPLICA-
TIONS.—The applicability of this section to an appli-
cation under section 505(j) is subject to subsection 
(i). 
‘‘(b) DEFINITIONS.—For purposes of this section: 
‘‘(1) ADVERSE DRUG EXPERIENCE.—The term 
‘adverse drug experience’ means any adverse event
249 
associated with the use of a drug in humans, wheth-
er 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 in-
tentional; 
‘‘(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 pharma-
cological action of the drug. 
‘‘(2) COVERED APPLICATION.—The term ‘cov-
ered application’ has the meaning indicated for such 
term in subsection (a)(1). 
‘‘(3) NEW
SAFETY
INFORMATION.—The term 
‘new safety information’ with respect to a drug 
means information about— 
‘‘(A) a serious risk or an unexpected seri-
ous risk associated with use of the drug that 
the Secretary has become aware of since the 
drug was approved, since the risk evaluation 
and mitigation strategy was required, or since
250 
the last assessment of the approved risk evalua-
tion 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 ad-
verse event 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 pro-
longation of existing hospitalization; 
‘‘(iv) a persistent or significant inca-
pacity or substantial disruption of the abil-
ity to conduct normal life functions; or 
‘‘(v) a congenital anomaly or birth de-
fect; or
251 
‘‘(B) based on appropriate medical judg-
ment, may jeopardize the patient and may re-
quire a medical or surgical intervention to pre-
vent 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; 
or 
‘‘(E) data derived from a postmarket risk 
identification and analysis system under section 
505(k)(3). 
‘‘(7) RESPONSIBLE
PERSON.—The term ‘re-
sponsible person’ has the meaning indicated for such 
term in subsection (e)(2). 
‘‘(8) UNEXPECTED SERIOUS RISK.—The term 
‘unexpected serious risk’ means a serious adverse
252 
drug experience that is not listed in the labeling of 
a drug, or that may be symptomatically and 
pathophysiologically related to an adverse drug expe-
rience identified in the labeling, but differs from 
such adverse drug experience because of greater se-
verity, specificity, or prevalence. 
‘‘(c) CONTENTS.—A proposed risk evaluation and 
mitigation strategy under subsection (a) shall— 
‘‘(1) include the timetable required under sub-
section (d); and 
‘‘(2) to the extent required by the Secretary, in-
clude additional elements described in subsections 
(e) and (f). 
‘‘(d) MINIMAL STRATEGY.—For purposes of sub-
section (c)(1), the risk evaluation and mitigation strategy 
for a drug shall require a timetable for submission of as-
sessments of the strategy that— 
‘‘(1) is not less frequent than once annually for 
the first 3 years after the strategy is initially ap-
proved; 
‘‘(2) includes an assessment in the seventh year 
after the strategy is so approved; and 
‘‘(3) subject to paragraph (2), for subsequent 
years—
253 
‘‘(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 de-
termines that serious risks of the drug have 
been adequately identified and assessed and are 
being adequately managed. 
‘‘(e) ADDITIONAL POTENTIAL ELEMENTS OF STRAT-
EGY.— 
‘‘(1) IN GENERAL.—The Secretary may under 
subsection (c)(2) require that the risk evaluation 
and mitigation strategy for a drug include 1 or more 
of the additional elements described in this sub-
section if the Secretary makes the determination re-
quired with respect to the element involved. 
‘‘(2) MEDGUIDE; PATIENT PACKAGE INSERT.— 
The risk evaluation and mitigation strategy for a 
drug may require that, as applicable, the person sub-
mitting the covered application or the holder of the 
approved such application (referred to in this section 
as the ‘responsible person’) develop for distribution 
to each patient when the drug is dispensed—
254 
‘‘(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 Sec-
retary determines that such insert may help 
mitigate a serious risk of the drug. 
‘‘(3) COMMUNICATION PLAN.—The risk evalua-
tion and mitigation strategy for a drug may require 
that the responsible person conduct a communica-
tion 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. Such plan may include— 
‘‘(A) sending letters to health care pro-
viders; 
‘‘(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 safe-
ty protocols (such as medical monitoring by 
periodic laboratory tests); or 
‘‘(C) disseminating information to health 
care providers through professional societies
255 
about any serious risks of the drug and any 
protocol to assure safe use. 
‘‘(f) RESTRICTIONS ON DISTRIBUTION OR USE.— 
‘‘(1) IN GENERAL.—If the Secretary determines 
that a drug shown to be effective can be safely used 
only if distribution or use of such drug is restricted, 
the Secretary may under subsection (c)(2) require as 
elements of the risk evaluation and mitigation strat-
egy such restrictions on distribution or use as are 
needed to ensure safe use of the drug. 
‘‘(2) ASSURING ACCESS AND MINIMIZING BUR-
DEN.—Elements of a risk evaluation and mitigation 
strategy included under paragraph (1) shall— 
‘‘(A) be commensurate with a specific seri-
ous risk listed in the labeling of the drug; 
‘‘(B) be posted publicly by the Secretary 
with an explanation of how such elements will 
mitigate the observed safety risk, which posting 
shall be made within 30 days after the date on 
which the Secretary requires the element in-
volved; 
‘‘(C) considering the risk referred to in 
subparagraph (A), not be unduly burdensome 
on patient access to the drug, considering in 
particular—
256 
‘‘(i) patients with serious or life- 
threatening diseases or conditions; and 
‘‘(ii) patients who have difficulty ac-
cessing 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, seri-
ous risks; and 
‘‘(ii) be designed to be compatible 
with established distribution, procurement, 
and dispensing systems for drugs. 
‘‘(3) ELEMENTS.—The restrictions on distribu-
tion or use described in paragraph (1) shall include 
1 or more goals to evaluate or mitigate a serious 
risk listed in the labeling of the drug, and may re-
quire that— 
‘‘(A) health care providers that prescribe 
the drug have special training or experience, or 
are specially certified, which training or certifi-
cation with respect to the drug is available to 
any willing provider from a frontier area;
257 
‘‘(B) pharmacies, practitioners, or health 
care settings that dispense the drug are spe-
cially certified, which training or certification 
with respect to the drug is available to any will-
ing provider from a frontier area; 
‘‘(C) the drug be dispensed to patients only 
in certain health care settings, such as hos-
pitals; 
‘‘(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 sub-
ject to certain monitoring; or 
‘‘(F) each patient using the drug be en-
rolled in a registry. 
‘‘(4) IMPLEMENTATION SYSTEM.—The restric-
tions on distribution or use described in paragraph 
(1) may require a system through which the respon-
sible person is able to— 
‘‘(A) monitor and evaluate implementation 
of the restrictions by health care providers, 
pharmacists, patients, and other parties in the 
health care system who are responsible for im-
plementing the restrictions;
258 
‘‘(B) work to improve implementation of 
the restrictions by health care providers, phar-
macists, patients, and other parties in the 
health care system who are responsible for im-
plementing the restrictions; and 
‘‘(C) notify wholesalers of the drug of 
those health care providers— 
‘‘(i) who are responsible for imple-
menting the restrictions; and 
‘‘(ii) whom the responsible person 
knows have failed to meet their responsibil-
ities for implementing the restrictions, 
after the responsible person has informed 
such party of such failure and such party 
has not remedied such failure. 
‘‘(5) LIMITATION.—No holder of an approved 
application shall use any restriction on distribution 
required by the Secretary as necessary to assure safe 
use of the drug to block or delay approval of an ap-
plication under section 505(b)(2) or (j) or to prevent 
application of such restriction under subsection 
(i)(1)(B) to a drug that is the subject of an abbre-
viated new drug application. 
‘‘(6) 
BIOEQUIVALENCE
TESTING.—Notwith-
standing any other provisions in this subsection, the
259 
holder of an approved application that is subject to 
distribution restrictions required under this sub-
section that limit the ability of a sponsor seeking ap-
proval of an application under subsection 505(b)(2) 
or (j) to purchase on the open market a sufficient 
quantity of drug to conduct bioequivalence testing 
shall provide to such a sponsor a sufficient amount 
of drug to conduct bioequivalence testing if the spon-
sor seeking approval under section 505(b)(2) or 
(j)— 
‘‘(A) agrees to such restrictions on dis-
tribution as the Secretary finds necessary to as-
sure safe use of the drug during bioequivalence 
testing; and 
‘‘(B) pays the holder of the approved appli-
cation the fair market value of the drug pur-
chased for bioequivalence testing. 
‘‘(7) LETTER BY SECRETARY.—Upon a showing 
by the sponsor seeking approval under section 
505(b)(2) or (j) that the sponsor has agreed to such 
restrictions necessary to assure safe use of the drug 
during bioequivalence testing, the Secretary shall 
issue to the sponsor seeking to conduct bioequiva-
lence testing a letter that describes the Secretary’s 
finding which shall serve as proof that the sponsor
260 
has satisfied the requirements of subparagraph 
(6)(A). 
‘‘(8) EVALUATION OF ELEMENTS TO ASSURE 
SAFE USE.—The Secretary, acting through the Drug 
Safety and Risk Management Advisory Committee 
(or any 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 ac-
cess to the drug; and 
‘‘(ii) to the extent practicable, mini-
mize 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
261 
‘‘(iii) to the extent practicable, mini-
mize the burden on the health care delivery 
system; and 
‘‘(C) considering such input and evalua-
tions— 
‘‘(i) issue or modify agency guidance 
about how to implement the requirements 
of this subsection; and 
‘‘(ii) modify elements under this sub-
section for 1 or more drugs as appropriate. 
‘‘(9) WAIVER
IN
PUBLIC
HEALTH
EMER-
GENCIES.—The Secretary may waive any restriction 
on distribution or use under this subsection during 
the period described in section 319(a) of the Public 
Health Service Act with respect to a qualified coun-
termeasure described under section 319F–1(a)(2) of 
such Act, to which a restriction or use 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 re-
quired to mitigate the effects of, or reduce the 
severity of, such public health emergency. 
‘‘(g) ASSESSMENT AND MODIFICATION OF APPROVED 
STRATEGY.—
262 
‘‘(1) VOLUNTARY ASSESSMENTS.—After the ap-
proval of a risk evaluation and mitigation strategy 
under subsection (a), the responsible person involved 
may, subject to paragraph (2), submit to the Sec-
retary 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 as-
sessment of, and may propose a modification to, the 
approved risk evaluation and mitigation strategy for 
a drug— 
‘‘(A) when submitting a supplemental ap-
plication for a new indication for use under sec-
tion 505(b) or under section 351 of the Public 
Health Service Act, unless the drug is not sub-
ject 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 determines
263 
that new safety or effectiveness information in-
dicates 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 strat-
egy; or 
‘‘(D) within 15 days when ordered by the 
Secretary, if the Secretary determines that 
there may be a cause for action by the Sec-
retary under section 505(e). 
‘‘(3) REQUIREMENTS FOR ASSESSMENTS.—An 
assessment under paragraph (1) or (2) of an ap-
proved risk evaluation and mitigation strategy for a 
drug shall include— 
‘‘(A) with respect to any goal under sub-
section (f), an assessment of the extent to 
which the restrictions on distribution or use are 
meeting the goal or whether the goal or such 
restrictions should be modified; 
‘‘(B) with respect to any postapproval 
study required under section 505(o)(3), the sta-
tus of such study, including whether any dif-
264 
ficulties completing the study have been en-
countered; and 
‘‘(C) with respect to any postapproval clin-
ical trial required under section 505(o), the sta-
tus of such clinical trial, including whether en-
rollment 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 section 
492C 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 assess-
ments of the strategy under subsection (d), in-
cluding to eliminate assessments; or 
‘‘(B) adding, modifying, or removing a re-
striction on distribution or use under subsection 
(f).
265 
‘‘(5) NO EFFECT ON LABELING CHANGES THAT 
DO NOT REQUIRE PREAPPROVAL.—In the case of a 
labeling change to which section 314.70 of title 21, 
Code of Federal Regulations (or any successor regu-
lation), applies for which the submission of a supple-
mental application is not required or for which dis-
tribution of the drug involved may commence upon 
the receipt by the Secretary of a supplemental appli-
cation for the change, the submission of an assess-
ment of the approved risk evaluation and mitigation 
strategy for the drug under paragraph (2) is not re-
quired. 
‘‘(h) REVIEW OF PROPOSED STRATEGIES; REVIEW 
OF ASSESSMENTS OF APPROVED STRATEGIES.— 
‘‘(1) 
IN
GENERAL.—The 
Secretary 
shall 
promptly review each proposed risk evaluation and 
mitigation strategy for a drug submitted under sub-
section (a) and each assessment of an approved risk 
evaluation and mitigation strategy for a drug sub-
mitted under subsection (g). 
‘‘(2) MARKETING PLAN.— 
‘‘(A) IN GENERAL.—As part of a review 
conducted under this subsection, the Secretary 
may require the applicant to submit informa-
tion regarding its marketing plan and practices
266 
for the drug, so as to allow the Secretary to de-
termine whether any of the proposed or ongoing 
marketing activities undermine any of the re-
quirements of the risk evaluation and mitiga-
tion strategy. 
‘‘(B) RULE OF CONSTRUCTION.—Subpara-
graph (A) may not be construed as authorizing 
the Secretary to make or direct any change in 
the marketing plan or practices involved. The 
preceding sentence does not affect any author-
ity of the Secretary under this Act, other than 
the authority of the Secretary under subpara-
graph (A). 
‘‘(3) DISCUSSION.—The Secretary shall initiate 
discussions with a responsible person for purposes of 
this subsection to determine a strategy— 
‘‘(A) if the proposed strategy is submitted 
as part of an application or supplemental appli-
cation under subsection (a) or subsection 
(g)(2)(A), not less than 60 days before the ac-
tion deadline for the application that has been 
agreed to by the Secretary and that has been 
set forth in goals identified in letters of the 
Secretary (relating to the use of fees collected 
under section 736 to expedite the drug develop-