Postmarketing Studies and  
Clinical TrialsImplementation  
of Section 505(o)(3) of the Federal 
Food, Drug, and Cosmetic Act 
Guidance for Industry 
 
 
 
 
DRAFT GUIDANCE
 
 
This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Ayanna Augustus at 301-796-3980 
or (CBER) Office of Communication, Outreach and Development at 800-835-4709 or 240-402-
8010. 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
October 2019 
Drug Safety 
Revision 1
877623dft.docx 
10/17/2019  Postmarketing Studies and 
Clinical TrialsImplementation 
of Section 505(o)(3) of the Federal 
Food, Drug, and Cosmetic Act 
Guidance for Industry 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
and/or 
 
Office of Communication, Outreach, and Development  
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Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
October 2019 
Drug Safety 
Revision 1
 
  TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 3 
A.  FDA May Require Postmarketing Studies and Clinical Trials ................................................. 3 
B.  Applicants Are Required to Report on the Status of Studies and Clinical Trials .................... 4 
III.  IMPLEMENTATION OF POSTMARKETING STUDY AND CLINICAL TRIAL 
REQUIREMENTS UNDER SECTION 505(O)(3) OF THE FD&C ACT .................. 6 
A.  Determining Whether Reports Under Section 505(k)(1) Are Sufficient ................................... 6 
1. Postmarketing Adverse Event Reports and the FDAs Adverse Event Reporting Systems .............. 6 
2. FDA Considerations in Determining Whether FAERS and VAERS Are Sufficient for the Purposes 
Under Section 505(o)(3)(B) of the FD&C Act in a Specific Circumstance ..................................... 7 
B.  Determining Whether the Active Postmarket Risk Identification and Analysis System 
Available Under Section 505(k)(3) Is Sufficient ................................................................................... 8 
1. The Sentinel System and the Active Postmarket Risk Identification and Analysis System ............... 8 
2. FDA Considerations in Determining Whether the ARIA System Is Sufficient ................................. 9 
a.  ARIA data characteristics needed to assess or identify a serious risk ....................................... 9 
b.  ARIA analytic capabilities needed to assess or identify a serious risk ..................................... 9 
3. Other Considerations About the Sufficiency of ARIA .................................................................... 10 
4. FDA Conduct of ARIA-Based Analyses of Similar Safety Concerns to Those Evaluated Under a 
PMR ............................................................................................................................................... 10 
5. FDA Conduct of Sentinel-Based Studies When a PMR Has Not Been Required ........................... 10 
6. Applicant Conduct of Analyses Using Other Electronic Health Care Systems ............................. 10 
C.  Examples of Postmarketing Requirements Under Section 505(o) of the FD&C Act ............. 11 
D.  Examples of Postmarketing Commitments ............................................................................... 16 
IV.  BENEFIT-RISK ASSESSMENT .................................................................................. 16 
V.  PROCEDURES ............................................................................................................... 17 
VI.  DISPUTE RESOLUTION ............................................................................................. 18 
VII.  ENFORCEMENT OF REQUIREMENTS FOR POSTMARKETING STUDIES 
AND CLINICAL TRIALS ............................................................................................. 18 
GLOSSARY................................................................................................................................. 20 
APPENDIX A:  PMR AND PMC AUTHORITIES ................................................................ 22 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Postmarketing Studies and Clinical TrialsImplementation of 
2  Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act 
3  Guidance for Industry1 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION 
18   
19  This guidance provides information on the implementation of section 505(o)(3) of the Federal 
20  Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 355(o)(3)),2 which authorizes FDA to 
21  require certain postmarketing studies and clinical trials3 for prescription drugs approved under 
22  section 505(c) of the FD&C Act and biological products approved under section 351 of the 
23  Public Health Service Act (the PHS Act) (42 U.S.C. 262).4   
24   
                                                 
1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for 
Biologics Evaluation and Research (CBER) at the Food and Drug Administration. 
 
2 Added by section 901 of Food and Drug Administration Amendments Act of 2007 (FDAAA). 
 
3 For purposes of implementing section 505(o)(3) of the FD&C Act, we distinguish between studies and 
clinical trials for the purposes described in this document. 
 
4 For the purposes of this guidance, all references to drugs include both human drugs and biological drug 
products regulated by CDER and CBER unless otherwise specified. 
 
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25  This guidance describes FDAs statutory authority to require certain postmarketing studies and 
26  clinical trials under section 505(o)(3) of the FD&C Act (i.e., postmarketing requirements 
27  (PMRs))5 and provides an overview of the types and purposes of such studies and clinical trials.  
28  This guidance also describes those types of postmarketing studies and clinical trials that are 
29  agreed upon (i.e., postmarketing commitments (PMCs))6 between FDA and the applicant.7 
30   
31  This draft guidance is a revision of the guidance for industry Postmarketing Studies and Clinical 
32  TrialsImplementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act 
33  published in April 2011.  This revised guidance provides information on implementation of 
34  sections 505(o)(3)(D)(i) and (ii) of the FD&C Act.  This guidance also reflects certain provisions 
35  enacted under the Substance Use-Disorder Prevention that Promotes Opioid Recovery and 
36  Treatment for Patients and Communities Act as they relate to postmarketing studies and clinical 
37  trials.8  This guidance does not distinguish between prescription drugs with active ingredients 
38  that are controlled substances and other prescription drugs because, at this time, the Agency does 
39  not intend to treat controlled substances differently than other prescription drugs under 505(o). 
40  Once finalized, this guidance will replace the April 2011 guidance.   
41   
42  This guidance does not apply to nonprescription drugs approved under a new drug application or 
43  to generic drugs approved under section 505(j) of the FD&C Act.   
44   
45  The Glossary defines many of the terms for purposes of this guidance.  Words or phrases found 
46  in the Glossary appear in bold italics at first mention. 
47   
48  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
49  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
50  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
51  the word should in Agency guidances means that something is suggested or recommended, but 
52  not required. 
53   
54   
                                                 
5 The term postmarketing requirement or PMR is used to describe all required postmarketing studies or clinical 
trials, including those required under FDAAA and those required under subpart H of 21 CFR part 314, subpart E of 
21 CFR part 601, the Pediatric Research Equity Act, and the animal efficacy rule (see Appendix A:  PMR and PMC 
Authorities). 
 
6 The term postmarketing commitment or PMC is used to describe studies and clinical trials that are agreed upon 
between FDA and the applicant (see Appendix A:  PMR and PMC Authorities). 
 
7 For the purposes of this guidance, for ease of reference, the term applicant refers to a responsible person as 
defined in section 505(o)(2)(A) of the FD&C Act (i.e., the holder of an application for a prescription drug approved 
under section 505(c) of the FD&C Act, or pending, and biological products licensed under section 351 of the PHS 
Act (42 U.S.C. 262), or pending). 
 
8 See Section 3041 of Public Law 115-271. 
 
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55  II.  BACKGROUND 
56   
57  A.  FDA May Require Postmarketing Studies and Clinical Trials 
58   
59  FDA approves drugs based upon a demonstration that the drug is safe and effective when used 
60  under the conditions specified in the proposed labeling.  In some instances, FDA may be aware 
61  of information and/or data at the time of approval or become aware of data and/or information in 
62  a postapproval setting that necessitates further assessment.  
63   
64  Under section 505(o)(3) of the FD&C Act, FDA, based on appropriate scientific data including 
65  information regarding chemically related or pharmacologically related drugs,9 can require at the 
66  time of approval that an applicant conduct postmarketing studies or clinical trials.  FDA may 
67  also require that an applicant conduct postmarketing studies or clinical trials for a drug product 
68  covered under an approved application if FDA becomes aware of new safety information.10   
69   
70  For example, in some cases, FDA may be concerned about a potential risk associated with the 
71  use of a drug and believe that the risk is serious but may not know enough about the risk, through 
72  adverse event reporting or otherwise, to determine how to address the risk in labeling and what 
73  information would be appropriate to include.  In such cases, FDA can require an applicant to 
74  conduct a postmarketing study or clinical trial to obtain more information about the risk.   
75   
76  Postmarketing studies and clinical trials may be required for any or all of the following three 
77  purposes:11 
78   
79    To assess a known serious risk related to the use of the drug 
80   
81    To assess signals of serious risk related to the use of the drug 
82   
83    To identify an unexpected serious risk when available data indicate the potential for a 
84  serious risk 
85   
86  For the purposes of this guidance,12 clinical trials and studies are defined as follows: 
87   
                                                 
9 See section 505(o)(3)(A) of the FD&C Act. 
 
10 See section 505(o)(3)(C) of the FD&C Act. New safety information is defined at section 505-1(b)(3) of the FD&C 
Act. 
 
11 See section 505(o)(3)(B) of the FD&C Act.  
 
12 These definitions of postmarketing clinical trial and study do not affect whether the trials or studies are subject to 
the requirements of Title VIII of FDAAA (Clinical Trial Databases) and section 402(j) of the PHS Act (42 U.S.C. 
282(j)). 
 
 
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88    Clinical trials are any prospective investigations in which the applicant or investigator 
89  determines the method of assigning the drug(s) or other interventions to one or more 
90  human subjects. 
91   
92    Studies are all other investigations, such as investigations with humans that are not 
93  clinical trials as defined above (e.g., observational epidemiologic studies), animal 
94  studies,13 and laboratory experiments.  
95   
96  Before requiring a postmarketing study, FDA must find that adverse event reporting under 
97  section 505(k)(1) of the FD&C Act and the active postmarketing risk identification and analysis 
98  system as available under section 505(k)(3) of the FD&C Act will not be sufficient to meet the 
99  purposes described above.14  Similarly, before requiring a postmarketing clinical trial, FDA must 
100  find that a postmarketing study or studies will not be sufficient to achieve these same purposes.15  
101   
102  In order to ensure that a study or clinical trial is well designed and adequate to address the 
103  serious risk, FDA describes the study or clinical trial to be conducted, including the study 
104  population and indication. 
105   
106  In general, the purposes of a PMR under section 505(o)(3) are related to serious risks.  The term 
107  serious risk is defined for purposes of section 505(o) as a risk  of a serious adverse drug 
108  experience.  This description does not mean that such postmarketing studies and clinical trials 
109  are limited to safety endpoints.  Rather, in some cases, a postmarketing study or clinical trial 
110  with efficacy endpoints may be appropriate, for example, to further assess whether a potential 
111  lack of expected pharmacological effect, including reduced effectiveness, may result in a serious 
112  adverse drug experience.16  
113   
114  B.  Applicants Are Required to Report on the Status of Studies and Clinical 
115  Trials 
116   
117  Under section 506B of the FD&C Act and 21 CFR 314.81(b)(2)(vii) and 601.70, applicants are 
118  required to report annually on the status of certain PMRs and PMCs, including PMRs required 
119  under section 505(o)(3) of the FD&C Act.  Under sections 506B(c), FDA is required to track 
120  these PMRs and PMCs and report on them annually in the Federal Register.17  
                                                 
13 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible.  FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible.  FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
 
14 See section 505(o)(3)(D)(i) of the FD&C Act.  
 
15 See section 505(o)(3)(D)(ii) of the FD&C Act.  
 
16 See sections 505(o)(2)(C) and 505-1(b)(5) of the FD&C Act. 
 
17 See the Postmarketing Requirements and Commitments web page at https://www.fda.gov/drugs/postmarket-
requirements-and-commitments/postmarketing-requirements-and-commitments-reports. 
 
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  Contains Nonbinding Recommendations 
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121   
122  Section 505(o)(3)(E)(ii) of the FD&C Act further delineates information that is required for 
123  PMRs that are issued under section 505(o)(3).  This information must include the following: 
124   
125    A timetable for completion 
126   
127  A set of milestone dates18 by which FDA measures progress of studies and clinical trials and 
128  compliance with requirements.  These goal dates generally include, but are not limited to, 
129  final protocol submission date, study or clinical trial completion date, and final report 
130  submission date.  Section 505(o)(3) of the FD&C Act does not include provisions allowing 
131  amendments to change milestone dates for purposes of required reporting.19  Therefore, 
132  status reporting under these regulations will remain based on the original schedule. 
133   
134    Periodic reports on the status of the study, including whether any difficulties in 
135  completing the study have been encountered 
136   
137    Periodic reports on the status of the clinical trial, including the following: 
138   
139    Whether enrollment has begun 

140   
141    The number of participants enrolled 

142   
143    The expected completion date 

144   
145    Whether any difficulties completing the clinical trial have been encountered 

146   
147    Registration information with respect to the clinical trial under section 402(j) of the 

148  PHS Act (42 U.S.C. 282(j)).20 
149   
150  In addition, section 505(o)(3)(E)(ii) of the FD&C Act requires that applicants submit a report on 
151  each study and clinical trial otherwise undertaken by the responsible person to investigate a 
152  safety issue, including postmarketing studies or clinical trials that are neither required by FDA 
153  nor agreed upon between FDA and the applicant.  The studies and clinical trials may include 
154  investigations initiated by an applicant for many reasons without prior discussion with or 
                                                 
18 For purposes of this guidance, milestone dates are a series of goal dates (e.g., final protocol submission, study or 
clinical trial completion date, final report submission) by which FDA measures progress of studies and clinical trials 
and compliance with requirements. 
 
19 21 CFR 314.81(b)(2)(vii)(a)(8)(ii-iii) and 21 CFR 601.70(b)(8)(ii-iii). 
 
20 Section 402(j) requires that certain clinical trial information, including information regarding results of clinical 
trials, be submitted to the clinical trials data bank (https://www.ClinicalTrials.gov).  Registration information for 
clinical trials required under section 505(o)(3) should include documentation that the PMR is registered in 
accordance with Title VIII of FDAAA.  See the guidance for sponsors, industry, researchers, investigators, and FDA 
staff Form FDA 3674  Certifications to Accompany Drug, Biological Product, and Device 
Applications/Submissions (June 2017). 
 
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Draft  Not for Implementation 
155  notification to FDA.  These studies and clinical trials may be summarized in a section of the 
156  annual report (drugs) or annual status report (biologics). 
157   
158  III.  IMPLEMENTATION OF POSTMARKETING STUDY AND CLINICAL TRIAL 
159  REQUIREMENTS UNDER SECTION 505(o)(3) OF THE FD&C ACT21 
160   
161  As discussed in section II.A, FDA May Require Postmarketing Safety Studies and Clinical 
162  Trials, FDA can require postmarketing studies and clinical trials for the following purposes:  to 
163  assess a known serious risk or signals of serious risk related to the use of the drug, or to identify 
164  an unexpected serious risk of a drug when available data indicate the potential for a serious risk.  
165  This determination will be based on scientific data deemed appropriate by FDA, including 
166  information regarding chemically related or pharmacologically related drug use. 
167   
168  Before requiring a postmarketing study or clinical trial under section 505(o)(3), FDA must find 
169  that the adverse event reporting under section 505(k)(1) of the FD&C Act and the analysis 
170  system under section 505(k)(3) of the FD&C Act (active risk identification and analysis (ARIA)) 
171  will not be sufficient to meet the aforementioned purposes.  Further, before requiring a 
172  postmarketing clinical trial, FDA must find that a postmarketing study or studies will not be 
173  sufficient to meet those purposes. 
174   
175  FDAs determination of whether the information available under subsections (k)(1) and (k)(3) is 
176  sufficient is based on analysis of multiple factors, including the following: the nature of the 
177  serious risk, the appropriate type of investigation to assess or identify the particular serious 
178  risk(s), the strengths and limitations of electronic health data and adverse event report data to 
179  assess the specific serious risk, the scientific tools available to evaluate this data, and the extent 
180  to which the available data informs the serious risk.  
181   
182  Certain types of questions related to serious risk may only be answerable through specific types 
183  of studies or clinical trials, and the information available under subsections (k)(1) and (k)(3) 
184  would generally be considered insufficient to address those questions.  For example, animal 
185  studies or clinical pharmacokinetic and pharmacodynamic trials may be the only means of 
186  determining whether a drug is carcinogenic or has the potential for interaction with other drugs, 
187  respectively.   
188   
189  A.  Determining Whether Reports Under Section 505(k)(1) Are Sufficient 
190   
191  1.  Postmarketing Adverse Event Reports and the FDAs Adverse Event Reporting 
192  Systems  
193   
                                                 
21 Applicants conducting postmarketing studies and clinical trials must continue to comply with 21 CFR parts 312 
and 58 when applicable and Health and Human Services (HHS) and FDA human subject protection regulations at 45 
CFR part 46 and 21 CFR parts 50 and 56 when applicable. 
 
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194  Section 505(k)(1) of the FD&C Act describes data that the applicant must report to FDA relating 
195  to clinical experience and other data or information associated with drugs.22  The regulations 
196  implementing section 505(k)(1) include, among other things, a requirement for applicants to 
197  submit adverse event information, electronically, to FDA.  The FDA Adverse Event Reporting 
198  System (FAERS) and Vaccine Adverse Event Reporting System (VAERS) databases23 contain 
199  individual case safety reports (ICSRs) that applicants submit based on information provided by 
200  consumers, patients, and health care providers.  These systems also contain ICSRs submitted 
201  directly to FDA by these reporters and ICSRs of adverse events reported in scientific literature 
202  and postmarketing studies.  FAERS and VAERS data include reports of medication errors 
203  or drug quality problems when these are associated with adverse events. 
204   
205  2.  FDA Considerations in Determining Whether FAERS and VAERS Are Sufficient 
206  for the Purposes Under Section 505(o)(3)(B) of the FD&C Act in a Specific 
207  Circumstance   
208   
209  The determination of the FAERSs and VAERSs sufficiency to meet the purposes described in 
210  section 505(o)(3)(B) of the FD&C Act is based, in the context of the serious risk related to the 
211  use of the particular drug, on considerations of the strengths and limitations of adverse event 
212  reports as information sources and on the particular data characteristics of the FAERS and 
213  VAERS systems.  Therefore, FDA determines the FAERSs and VAERSs sufficiency for the 
214  purposes of whether to require a postmarketing study or clinical trial on a case-by-case basis for 
215  each serious risk. 
216   
217  Adverse event reports may be sufficient for identifying and assessing new (e.g., unexpected, 
218  unlabeled), serious adverse drug events that occur rarely and are closely linked in time to 
219  initiation of the drug and for which the background rate of events is low.  Examples include 
220  Stevens-Johnson syndrome and toxic epidermal necrolysis. 
221   
222  Limitations of adverse event report data include the following: 
223   
224    Cannot be used to calculate the actual incidence rate of an adverse event, including the 
225  incidence with a particular drug or to conduct comparisons between drugs on the rate of 
226  occurrence of an adverse event based on the total number of people exposed to the drug 
227  who experienced an adverse event (numerator) and the total number of people exposed to 
228  the drug (denominator).  For example: 
229   
230    There is no certainty that a reported adverse event is due to the drug because FDA 

231  does not require a causal relationship between the drug and event be proven as part of 
232  the reporting requirements 
                                                 
22 The requirements for postmarketing adverse event reporting are described in 21 CFR 310.305, 314.80, 314.81, 
314.98, and 600.80. 
 
23 The regulations implementing section 505(k)(1) of the FD&C Act also refer to periodic adverse drug experience 
reports for approved drugs.  Periodic safety reports summarize postmarket safety experience with a drug during a 
defined period of time and largely comprise listings and summary analyses of the adverse event reports submitted to 
the FAERS and VAERS.  Consequently, FDAs determination of the sufficiency of the FAERS and VAERS 
encompasses the information that would generally be included in periodic safety reports. 
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233   
234    Lack of adequate detail on adverse events reported to FDA 

235   
236    Underreporting of adverse events to FDA 

237   
238    Stimulated reporting of adverse events (e.g., after significant publicity of a potential 

239  drug risk) 
240   
241    The FAERS and VAERS databases do not collect information about the total number 

242  of people exposed to the drug 
243   
244    Frequently have incomplete or missing information that affects the following:  
245   
246    Assessment of potentially relevant risk factors and confounders necessary to 

247  determine whether a causal relationship exists between a drug and an adverse event 
248   
249     Identification of patient subpopulations (e.g., elderly patients, patients with specific 

250  comorbidities) and evaluation of potential differential risk of the adverse event 
251   
252    Evaluation of potential drug interactions 

253   
254  B.  Determining Whether the Active Postmarket Risk Identification and Analysis 
255  System Available Under Section 505(k)(3) Is Sufficient 
256   
257  1.  The Sentinel System and the Active Postmarket Risk Identification and Analysis 
258  System  
259   
260  FDA established the Sentinel System (Sentinel), a comprehensive active surveillance system, to 
261  complement FDAs existing postmarket capabilities and to monitor the safety of approved drugs 
262  using large sets of electronic health care data.24  Sentinels analytic capabilities are broad and 
263  range from simple, rapid queries (e.g., counts of exposures) to sophisticated traditional 
264  pharmacoepidemiologic studies that include medical record validation.   
265   
266  Within Sentinel, the ARIA system comprises predefined, parameterized, reusable routine 
267  querying tools combined with the electronic data in the Sentinel Common Data Model.25, 26  
                                                 
24 See the FDAs Sentinel Initiative Background web page at https://www.fda.gov/safety/fdas-sentinel-
initiative/fdas-sentinel-initiative-background.   
 
25 Information about the ARIA analytic tools is available on the FDAs Sentinel web page at 
https://www.sentinelinitiative.org/active-risk-identification-and-analysis-aria.  
 
26 The Sentinel Common Data Model is the standardized data structure employed by all the Sentinel participants 
(Data Partners).  The Data Partners transform the data in their local existing environments according to the Common 
Data Model, which enables them to execute standardized computer programs that run identically at each Data 
Partner site.  Information about the Common Data Model is available at 
https://www.sentinelinitiative.org/sentinel/data/distributed-database-common-data-model.   
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268  FDA considers the ARIA system to be the active postmarket risk identification and analysis 
269  system for the purposes of section 505(k)(3) of the FD&C Act.   
270   
271  2.  FDA Considerations in Determining Whether the ARIA System Is Sufficient  
272   
273  The determination of the ARIA systems sufficiency to meet the purposes described in section 
274  505(o)(3)(B) of the FD&C Act, is based on an assessment of the capabilities of the system (i.e., a 
275  combination of the electronic health care data available in the Sentinel Common Data Model and 
276  analytic methods) that exist at the time of the sufficiency assessment.  This determination is 
277  made on a case-by-case basis and takes into consideration multiple factors, some of which may 
278  be uncertain at the time of the sufficiency assessment (e.g., the future uptake of a newly 
279  approved drug, subsequent exposure of patients to a drug). 
280   
281  a.  ARIA data characteristics needed to assess or identify a serious risk 
282   
283  With respect to the electronic health care data characteristics, FDA considers the following when 
284  determining the sufficiency of the ARIA system in a particular case: 
285   
286     Is it possible to identify exposure to the drug within the available data?   
287   
288    Is a validated or sufficiently defined health outcome of interest identifiable within the 
289  available data?   
290   
291    Are sufficient data available in the ARIA system on important confounders, and to what 
292  extent might these confounders influence the outcome of the study?  
293   
294    Is the population (i.e., cohort) of interest identifiable within the available data?   
295   
296    Can an appropriate reference population be identified within the available data to make 
297  risk-based comparisons?   
298   
299    Is there sufficient statistical power to assess the questions of interest?   
300   
301    Is there sufficient patient follow-up time (i.e., duration of observation time after medical 
302  product exposure) in the ARIA system to inform the question of interest? 
303   
304  b.  ARIA analytic capabilities needed to assess or identify a serious risk 
305   
306  FDA considers the following with respect to the analysis tools when determining the sufficiency 
307  of the ARIA system for the purposes under section 505(o)(3)(B): 
308   
309    Are the analysis tools currently available through the ARIA system adequate for 
310  assessing the serious risk?  
311   
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312  3.  Other Considerations About the Sufficiency of ARIA 
313   
314  Another important consideration is whether electronic health care data systems available to FDA 
315  have the capacity to manage the FDAs need for multiple, concurrent, and relatively rapid ARIA 
316  queries.  The number of proposed analyses may exceed ARIAs capacity.  If this will occur, 
317  FDA may consider requiring a postmarketing study. 
318   
319  If, after the original determination of sufficiency, FDA determines the ARIA systems analytic 
320  methods and/or Sentinels data are insufficient to meet the purposes in section 505(o)(3)(B) of 
321  the FD&C Act, FDA may require a postmarketing study or clinical trial. 
322   
323  4.  FDA Conduct of ARIA-Based Analyses of Similar Safety Concerns to Those 
324  Evaluated Under a PMR 
325   
326  Even after requiring that an applicant conduct a postmarketing study or clinical trial for a 
327  particular purpose, FDA may also perform ARIA analyses as part of its pharmacovigilance 
328  activities for a drug to further evaluate the drugs safety.  That is, even if the FDA considers the 
329  ARIA system insufficient to adequately address a specific serious risk (based upon the 
330  considerations above) and a PMR is issued, the ARIA system may still play a role in 
331  understanding a broader or related aspect of the issue. 
332   
333  For example, evaluation of a specific safety concern may need to be assessed within both the 
334  intended general population and a subpopulation.  FDA may require an applicant to conduct a 
335  postmarketing study or clinical trial to assess a serious risk in a specific subpopulation that 
336  cannot be identified in ARIA and FDA may perform its own assessment of the same safety 
337  concern in the general population using the ARIA system.  In this example, FDA would issue a 
338  PMR focusing on the specific subpopulation but would not issue a PMR for the related 
339  assessment of the safety concern in the general population.  The combination of the information 
340  obtained from the postmarketing study or clinical trial performed by the applicant with the 
341  information FDA obtains from its own assessment within ARIA would provide a more 
342  comprehensive understanding of the serious risk at issue. 
343   
344  5.  FDA Conduct of Sentinel-Based Studies When a PMR Has Not Been Required  
345   
346  FDA may use analyses to study the safety of a drug using the Sentinel system when a PMR is not 
347  required.  These studies may be useful to gather additional safety information or clarify 
348  observations that were made at the time of approval.  FDA studies using Sentinel may also help 
349  identify and/or assess safety outcomes when drugs are used more broadly than was studied 
350  during drug development. 
351   
352  6.  Applicant Conduct of Analyses Using Other Electronic Health Care Systems 
353   
354  An FDA determination, with regard to a particular drug, that the ARIA system is insufficient to 
355  meet the purposes under section 505(o)(3)(B) of the FD&C Act does not necessarily represent 
356  the following conclusions: 
357   
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358    That analyses using any type of administrative claims or electronic health care database 
359  will be insufficient to evaluate the serious risk.   
360   
361    The characteristics of, and the data contained within, electronic health care databases 

362  differ, as do available analytic methods.   
363   
364    FDA may determine that an applicant could conduct a postmarketing study utilizing 

365  data from other electronic health care systems and require a PMR. 
366   
367    That the administrative claims and health care databases that comprise the ARIA system 
368  are insufficient as an information source.  Safety evaluations that use non-ARIA analytic 
369  methods to analyze those databases may be appropriate.  In those cases, FDA may 
370  determine that an applicant could conduct a postmarketing study using these other 
371  databases and require a PMR. 
372   
373  In summary, to obtain more information about a known serious risk, a signal of a serious risk, or 
374  an unexpected serious risk associated with the use of a drug, FDA can require applicants to 
375  conduct (1) a postmarketing study or studies after the Agency has determined that neither 
376  adverse event report data nor the ARIA system will be sufficient for such purpose, or (2) a 
377  postmarketing clinical trial or trials after it has determined that a postmarketing study or studies 
378  will not be sufficient for such purpose. 
379   
380  C.  Examples of Postmarketing Requirements Under Section 505(o) of the 
381  FD&C Act 
382   
383  This section describes examples of postmarketing studies and clinical trials that FDA will 
384  generally consider requiring under section 505(o)(3) of the FD&C Act. 
385   
386  Examples of postmarketing studies include the following: 
387   
388    Safety studies in animals investigating specific end-organ toxicities 
389   
390  These studies include, but are not limited to, carcinogenicity and reproductive toxicity 
391  studies.  Although in most instances applicants complete these studies before marketing 
392  approval, the studies could be conducted postapproval for certain drugsfor example, 
393  drugs intended to treat serious and life-threatening diseases.27  If conducted postapproval, 
394  these studies would be required under 505(o) of the FD&C Act.  Examples include 
395  studies designed to do the following: 
396   
397    Assess carcinogenic potential in appropriate species (e.g., mice and rats) 

398   
399    Assess the potential for reproductive toxicology in appropriate species (e.g., monkeys 

400  or rabbits) 
401   
                                                 
27 See the ICH guidance for industry S1A The Need for Long-Term Rodent Carcinogenicity Studies of 
Pharmaceuticals (March 1996). 
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402    In vitro laboratory safety studies designed to do the following: 
403   
404    Assess certain receptor affinities for any circulating or major metabolites, including 

405  conjugates, to evaluate the potential for off-target binding and resulting serious risk 
406   
407    Determine whether resistance to a drug has developed in those organisms specific to 

408  the labeled indication, resulting in increased serious risk 
409   
410    Define the mechanism of drug resistance for certain organisms 

411   
412    Assess the risk of cross contamination between drugs that could result from sharing 

413  drug-contacting equipment and parts 
414   
415    Validate the accuracy, precision, sensitivity, specificity, and robustness of an 

416  immunogenicity assay for a drug to assess an immunologic safety concern 
417   
418    Observational pharmacoepidemiologic studies 
419   
420  Such studies are generally designed to assess a serious risk associated with a drug 
421  exposure or quantify risk or evaluate factors that affect this risk (e.g., drug dose, timing of 
422  exposure, patient characteristics).  Data sources for observational studies could include 
423  administrative health care claims data, electronic medical records, registries, 
424  prospectively collected observational data, or other sources of observational information. 
425   
426  Applicants should consider the following when designing pharmacoepidemiologic 
427  studies.28 
428   
429    To facilitate interpretation of the findings, the studies should always have protocols 

430  (including a statistical analysis plan), should include control groups, and should test 
431  prespecified hypotheses.  A control group may be omitted when there is a 
432  scientifically valid reason.   
433   
434    For a solely descriptive study, instead of one with a prespecified hypothesis, the 

435  protocol may include clearly stated objectives for describing the safety issue, 
436  including a defined upper bound for detectable risk, if applicable.   
437   
438  Registries29 are a type of prospective pharmacoepidemiologic study.  Applicants should 
439  consider the following points in the use of registry studies: 
440   
                                                 
28 See also the guidance for industry and FDA staff Best Practices for Conducting and Reporting 
Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data. (May 2013). 
 
29 Registries established with the primary purpose of enrolling patients to mitigate a serious risk associated with a 
drug would be required as part of a REMS under section 505-1(f)(3)(F).  When part of a REMS, they are an element 
necessary for the safe use of the drug and are not designed as a study with completion dates.  These types of 
registries would not be required as PMRs and are not described further in this guidance. 
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441    FDA may approve a drug with a requirement for a registry that would collect data for 

442  a study required as a PMR (under section 505(o)(3) of the FD&C Act).  When a 
443  pharmacoepidemiologic study using registry data meets the statutory criteria for a 
444  PMR described in section III., Implementation of Postmarketing Study and Clinical 
445  Trial Requirements Under Section 505(o)(3) of the FD&C Act, FDA intends to 
446  require the registry and the study as a PMR. 
447   
448    A sponsor can voluntarily create a registry to serve as a repository for clinical data, 

449  such as an outcomes registry, that is not part of a PMR issued under section 505(o)(3) 
450  of the FD&C Act.  However, if FDA becomes aware of new safety information in the 
451  postapproval setting, FDA could require the sponsor to conduct a PMR study, which 
452  may utilize the registry data. 
453   
454  Other examples of required observational pharmacoepidemiologic studies include, but are 
455  not necessarily limited to, studies designed to do the following: 
456   
457    Provide estimates of absolute risk (e.g., incidence rates) for a serious adverse event or 

458  toxicity or provide estimates of relative risk 
459   
460    Obtain long-term clinical outcome data, including information about potentially rare 

461  serious adverse events, in patients exposed to the drug compared to patients not 
462  exposed to the drug 
463   
464    Identify risk factors (e.g., patient characteristics, duration of drug use) associated with 

465  the occurrence of adverse events among patients exposed to specified drugs 
466   
467    Compare pregnancy incidence, pregnancy outcomes, and/or child outcomes for 

468  patients exposed to the drug compared to patients not exposed to the drug 
469   
470    Meta-analyses 
471   
472  Meta-analyses30 are studies that can be designed to evaluate a safety endpoint by 
473  statistical analysis of data from completed studies or clinical trials.  A meta-analysis 
474  should use a prospectively designed study protocol and analysis plan with a 
475  comprehensive selection of relevant studies or clinical trials and appropriate statistical 
476  methodology.  An example of a required meta-analysis is one designed to:  
477   
478    Evaluate the occurrence of all-cause mortality, cardiovascular death, and cancer 

479  incidence and identify potential predictive factors in patients treated with the drug 
480  compared to control therapies in all completed randomized clinical trials that include 
481  the drug 
482   
                                                 
30 See the draft guidance for industry Meta-Analyses of Randomized Controlled Clinical Trials to Evaluate the 
Safety of Human Drugs or Biological Products (November 2018).  When final, this guidance will represent the 
FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
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483  Postmarketing clinical trials required under section 505(o)(3) of the FD&C Act to assess or 
484  identify a serious risk typically have a safety endpoint evaluated with prespecified assessments 
485  and are adequately powered to analyze the serious risk identified by FDA.  In some cases, when 
486  a serious risk relates to failure of expected pharmacological action, including reduced 
487  effectiveness, the trial might be designed with an efficacy endpoint, for example, to further 
488  assess whether a potential failure of expected pharmacological action, including reduced 
489  effectiveness, may result in a serious adverse drug experience.   
490   
491  Examples of clinical trials designed with safety endpoints include trials intended to: 
492   
493    Evaluate, in a controlled clinical trial, the occurrence of asthma exacerbations 

494  associated with potential serious adverse effects of the irritative component of an 
495  inhalation treatment for asthma  
496   
497    Determine the incidence of myocardial infarction in patients treated with the 

498  approved drug in a follow-on clinical trial after approval, using the original 
499  randomized population 
500   
501    Evaluate differences in safety outcomes between patients who are randomized after a 

502  defined period of treatment to either placebo or continued treatment (randomized 
503  withdrawal trial) 
504   
505    Evaluate the potential for QT interval prolongation in a thorough QT clinical trial 

506   
507    Measure growth and neurocognitive function in pediatric patients treated chronically 

508  with the drug31 
509   
510    Evaluate safety in a particular racial or ethnic group or vulnerable population such as 

511  the immunocompromised31 
512   
513    Evaluate the safety of the drug in pregnant women31 

514   
515    Evaluate drug toxicity in patients with hepatic or renal impairment31 

516   
517    Evaluate long-term safety of cell and gene therapy products depending on the type of 

518  vector used and the inherent risk of integration 
519   
520    Evaluate the safety of a drug in patients with HIV-1 coinfected with hepatitis C or B31 

521   
522  Examples of clinical trials intended to further assess or identify a serious risk related to failure of 
523  expected pharmacological action, including reduced effectiveness, could be designed to do the 
524  following: 
525   
                                                 
31 Patients are treated with the drug at a dose and schedule specified in the clinical trial protocol. 
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526    Determine whether extending the treatment duration of an antiviral drug, which is 

527  indicated to treat a serious viral infection, mitigates the risk for relapse after 
528  completing the course of treatment 
529   
530    Evaluate a newly identified potential drug-drug interaction that may reduce the 

531  systemic exposure of a drug approved to reduce the risk of cardiovascular events  
532   
533    Evaluate a newly identified antidrug antibody response to a biological drug product 

534  approved to treat a serious disease, when information suggests that the antibody may 
535  reduce the drugs effectiveness either by altering its pharmacokinetics or by binding 
536  to domains of the drug critical to its functional activity 
537   
538    Evaluate a new signal that a subgroup of patients (e.g., defined by age, sex, race, 

539  biomarker) with a life-threatening cancer may not respond to a drug that had been 
540  approved based on a clinically meaningful effect in the overall population with the 
541  cancer, such that certain patients may be exposed to toxicity with less prospect for 
542  benefit 
543   
544  The following describe examples of evaluations designed for the purposes under section 
545  505(o)(3) of the FD&C Act that could be required as either a postmarketing study or clinical 
546  trial, depending on the type of information and/or data necessary to assess the risk being 
547  addressed by the PMR: 
548   
549    PMRs designed to evaluate the pharmacokinetics of the drug in the labeled population or 
550  in a subpopulation at potential risk for high drug exposures that could lead to toxicity.  
551  These could include studies or clinical trials designed to do the following: 
552   
553    Determine the optimal dose for maintenance therapy in patients with chronic renal 

554  disease, a population at risk for drug accumulation 
555   
556    Study the pharmacokinetic profile in a rodent model of hepatic dysfunction to 

557  evaluate the potential for toxicity in patients with liver impairment 
558   
559    PMRs designed to evaluate drug interactions or bioavailability when scientific data 
560  indicate the potential for a serious safety risk.  These could include studies or clinical 
561  trials to do the following: 
562   
563    Assess in vitro whether drugs are p-glycoprotein substrates and therefore could lead 

564  to increased drug concentrations and toxicity 
565   
566    Assess potential interactions of an approved drug with a frequently concomitantly 

567  prescribed medication 
568   
569    Evaluate whether multiple doses of an approved drug alter the metabolism of a 

570  sensitive cytochrome P450 2C9 substrate 
571   
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572    Evaluate bioavailability of an oral drug in the presence of food 

573   
574  D.  Examples of Postmarketing Commitments 
575   
576  In general, the following types of studies or clinical trials can be considered for agreed-upon 
577  PMCs: 
578   
579    Drug and biologic product quality studies, including manufacturing, stability, and 
580  immunogenicity studies that do not have a primary safety endpoint, such as studies 
581  designed to do the following: 
582   
583    Develop an optical rotation test, collect data on commercial batches, and use the data 

584  to update drug substance specification standards 
585   
586    Evaluate immune response to concomitant vaccination or vaccinations that are a part 

587  of routine U.S. immunization practice 
588   
589    Pharmacoepidemiologic studies designed to examine the natural history of a disease or to 
590  estimate background rates for adverse events in a population not treated with the drug 
591  that is the subject of the marketing application 
592   
593    Studies and clinical trials conducted with vaccines, such as surveillance and observational 
594  pharmacoepidemiologic studies when data do not suggest a serious risk or signals of 
595  serious risk related to the use of the vaccine and when available data do not indicate the 
596  potential for serious risk, such as the following: 
597   
598    A surveillance study of cases of the infectious disease targeted by the approved 

599  vaccine occurring in vaccinated populations using product-specific surveys and 
600  calculating product-specific rates of infectious disease within the monitored 
601  population 
602   
603    A clinical trial conducted with vaccines in which the objective is a further 

604  characterization of the safety profile and the primary endpoint is not related to a 
605  serious risk identified by FDA under section 505(o) of the FD&C Act 
606   
607   
608  IV.  BENEFIT-RISK ASSESSMENT 
609   
610  The intent of a PMR is to achieve a better understanding and more fully characterize a serious 
611  risk, if one exists.  FDA will review the data and/or information obtained under a PMR and 
612  assess its effect on the benefit-risk profile of the drug in the context of the serious risk being 
613  evaluated.  This may result, for example, in labeling changes under section 505(o)(4) of the 
614  FD&C Act.  
615   
616   
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617  V.  PROCEDURES 
618   
619  The following general PMR and PMC procedures apply to PMRs issued under section 505(o)(3) 
620  of the FD&C Act. 
621   
622  For new marketing applications, FDA plans to inform the applicant of the planned target date for 
623  communication of feedback from the review division regarding PMRs and PMCs in the filing 
624  communication letter.32   
625   
626  In both the pre- and postapproval settings, FDA plans to communicate a list of potential PMRs 
627  and PMCs, clearly delineated as to which are required and which may be agreed upon, to the 
628  applicant along with a brief rationale for why FDA thinks these studies and clinical trials are 
629  appropriate.  The list should also include a request for a proposed timetable for completion. 
630   
631  The applicant will have the opportunity to discuss the design and conduct of the PMRs and 
632  PMCs, as well as the overall goal, with the FDA review team.  The applicant should provide 
633  prompt feedback and engage in discussion as needed with the FDA review team to facilitate 
634  completion of clearly written and well-designed PMRs and PMCs.  The applicant should also 
635  provide a timetable for completion of the study or clinical trial for the PMRs and a schedule for 
636  milestone submissions and final reports for PMCs.  For PMRs and PMCs, the first milestone is 
637  generally the final protocol submission date.  FDA considers the term final to mean that the 
638  applicant has submitted a protocol, the FDA review team has sent comments to the applicant, and 
639  the protocol has been revised as needed to meet the goal of the study or clinical trial.  Thus, the 
640  date for this milestone should be selected to allow for the discussion period needed to create a 
641  well-designed study or clinical trial.  As described in section II.B., Applicants Are Required to 
642  Report on the Status of Studies and Clinical Trials, public status of PMRs and PMCs is based on 
643  the original schedule, so appropriate and realistic dates should be proposed. 
644   
645  The FDA review team intends to (1) review the potential study or clinical trial designs to make 
646  sure they will serve the purposes of the study or clinical trial and (2) assess whether the proposed 
647  timetable will be realistic and will provide for timely completion of the study or clinical trial. 
648   
649  Section 505(o)(3) of the FD&C Act gives FDA the authority to require PMRs without prior 
650  agreement from the applicant.  For PMCs, the applicant should submit a written agreement to 
651  conduct the PMCs.  FDA intends to include the PMRs and PMCs and their milestones and dates 
652  in the action letter issued at the completion of the application review.  In the postapproval setting, 
653  FDA intends to include the new PMRs and PMCs and their milestones and dates in the letter 
654  establishing the PMRs and PMCs.  
655   
656   
                                                 
32 See CDER Manual of Policies and Procedures (MAPP) 6010.8 Rev. 1 NDAs and BLAs: Communications to 
Applicants of Planned Review Timelines.  For this and other MAPPs, see the CDER MAPPs web page at: 
https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/cder-manual-policies-procedures-mapp.  
 
 
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657  VI.  DISPUTE RESOLUTION 
658   
659  The applicant may appeal a requirement to conduct a postmarketing study or clinical trial using 
660  the usual dispute resolution procedures (see the guidance for industry and review staff Formal 
661  Dispute Resolution:  Appeals Above the Division Level (November 2017))33 (see section 
662  505(o)(3)(F) of the FD&C Act). 
663   
664   
665  VII.  ENFORCEMENT OF REQUIREMENTS FOR POSTMARKETING STUDIES 
666  AND CLINICAL TRIALS 
667   
668  FDA has authority to enforce the section 505(o)(3)(E)(ii) requirements for postmarketing studies 
34
669  and clinical trials.   An applicants failure to comply with the timetable, periodic report 
670  submissions, and other requirements of section 505(o)(3)(E)(ii) of the FD&C Act will be 
671  considered a violation unless the applicant demonstrates good cause for the noncompliance.  
672  Section 505(o)(3)(E)(ii) of the FD&C Act provides that FDA shall determine what constitutes 
673  good cause.  In addition, under section 505(p)(2) of the FD&C Act, failure to conduct a 
674  postmarketing study or clinical trial required under section 506B of the FD&C Act and subparts 
675  H and E (21 CFR 314.510 and 601.41) may result in enforcement action. 
676   
677  Enforcement action could include one or more of the following: 
678   
679    Charges under section 505 of the FD&C Act.  A responsible person35 may not introduce 
680  or deliver into interstate commerce the drug involved if the person is in violation of 
681  section 505(o) (postmarketing study and clinical trial requirements) (see section 
682  505(o)(1) of the FD&C Act) or 505(p)(2) (certain postmarketing studies). 
683   
684    Misbranding charges.  A drug is misbranded under section 502(z) of the FD&C Act (21 
685  U.S.C. 332(z)) if the applicant for that drug violates postmarketing study or clinical trial 
686  requirements, including those outlined in section II.B., Applicants Are Required to 
687  Report on the Status of Studies and Clinical Trials. 
688   
689    Civil monetary penalties.  Under section 303(f)(4)(A) of the FD&C Act (21 U.S.C. 
690  333(f)(4)(A)), an applicant that violates postmarketing study or clinical trial requirements 
691  may be subject to civil monetary penalties of up to $250,000 per violation, but no more 
692  than $1 million for all violations adjudicated in a single proceeding.  These penalties 
693  increase if the violation continues more than 30 days after FDA notifies the applicant of 
694  the violation.  The penalties double for the following 30-day period and continue to 
                                                 
33 When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents. 
 
34 FDA has the authority to review records upon inspection of postmarketing studies and clinical trials, including 
underlying data and source documents (see section 505(k) of the FD&C Act). 
 
35 Defined at section 505(o)(2)(A) of the FD&C Act. 
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695  double for subsequent 30-day periods, up to $1 million per period and $10 million for all 
696  violations adjudicated in a single proceeding.  In determining the amount of a civil 
697  penalty, FDA will consider the applicants efforts to correct the violation (see section 
698  303(f)(4)(B) of the FD&C Act). 
699   
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700  GLOSSARY1 
701   
702  Adverse drug experience is any adverse event associated with the use of a drug in humans, 
703  whether or not considered drug related, including: 
704   
705  (A) an adverse event occurring in the course of the use of the drug in professional practice; 
706   
707  (B) an adverse event occurring from an overdose of the drug, whether accidental or 
708  intentional; 
709   
710  (C) an adverse event occurring from abuse of the drug; 
711   
712  (D) an adverse event occurring from withdrawal of the drug; and 
713   
714  (E) any failure of expected pharmacological action of the drug, which may include reduced 
715  effectiveness under the conditions of use prescribed in the labeling of such drug, but 
716  which may not include reduced effectiveness that is in accordance with such labeling. 
717   
718  Clinical trials are any prospective investigations in which the applicant or investigator 
719  determines the method of assigning the drug or drugs or other interventions to one or more 
720  human subjects.  Clinical trials are one type of clinical investigation, as defined at 21 CFR 
721  312.3(b).   
722   
723  New safety information with respect to a drug, means information derived from a clinical trial, 
724  an adverse event report, a postapproval study (including a study under section 505(o)(3) of the 
725  FD&C Act), or peer-reviewed biomedical literature; data derived from the postmarket risk 
726  identification and analysis system under section 505(k) of the FD&C Act; or other scientific data 
727  deemed appropriate by FDA about 
728   
729  (A) a serious risk or unexpected serious risk associated with use of the drug that FDA has 
730  become aware of (that may be based on a new analysis of existing information) since the 
731  drug was approved, since the risk evaluation and mitigation strategy was required, or 
732  since the last assessment of the approved risk evaluation and mitigation strategy for the 
733  drug; or 
734   
735  (B) the effectiveness of the approved risk evaluation and mitigation strategy for the drug 
736  obtained since the last assessment of such strategy. 
737   
                                                 
1 The definitions in this glossary are presented for purposes of this guidance only.  The definitions of the following 
terms are adapted from section 505-1(b) of the FD&C Act (21 U.S.C. 355-1(b)): adverse drug experience, new 
safety information, serious adverse drug experience, serious risk, signal of a serious risk and unexpected serious 
risk.  FDA considers these definitions to include safety information related to a class effect, not apparently limited to 
a single member of the class for structural, mechanistic, or other reasons. 
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738  Serious adverse drug experience is an adverse drug experience that  
739   
740  (A) results in 
741  (i) death; 
742  (ii) an adverse drug experience that places the patient at immediate risk of death from the 
743  adverse drug experience as it occurred (not including an adverse drug experience that 
744  might have caused death had it occurred in a more severe form); 
745  (iii) inpatient hospitalization or prolongation of existing hospitalization;  
746  (iv) a persistent or significant incapacity or substantial disruption of the ability to conduct 
747  normal life functions; or 
748  (v) a congenital anomaly or birth defect; or 
749   
750  (B) based on appropriate medical judgment, may jeopardize the patient and may require a 
751  medical or surgical intervention to prevent an outcome described under subparagraph (A). 
752   
753  Serious risk means a risk of a serious adverse drug experience. 
754   
755  Signal of a serious risk means information related to a serious adverse drug experience 
756  associated with use of a drug and derived from  
757   
758  (A) a clinical trial; 
759   
760  (B) adverse event reports; 
761   
762  (C) a postapproval study, including a study under section 505(o)(3) of the FD&C Act; 
763   
764  (D) peer-reviewed biomedical literature; 
765   
766  (E) data derived from the postmarket risk identification and analysis system under section 
767  505(k)(4) of the FD&C Act; 
768   
769  (F) other scientific data deemed appropriate by the Secretary. 
770   
771  Studies are all other (not clinical trial) investigations, such as investigations with humans that are 
772  not clinical trials as defined above (e.g., observational epidemiologic studies), animal studies, 
773  and laboratory experiments. 
774   
775  Unexpected serious risk means a serious adverse drug experience that is not listed in the labeling 
776  of a drug or that may be symptomatically and pathophysiologically related to an adverse drug 
777  experience identified in the labeling, but differs because of greater severity, specificity, or 
778  prevalence. 
779   
780   
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781  APPENDIX A:  PMR AND PMC AUTHORITIES 
782   
Postmarketing Requirement  Postmarketing Commitment 
(PMR) Authorities  (PMC) Authorities 
Pediatric Research under section 505B of the  Agreed -upon postmarketing studies and 
Federal Food, Drug, and Cosmetic Act (the  clinical trials: 
FD&C Act):1   
    21 CFR 312.85 
  21 CFR 314.55(b) (drugs) 
  21 CFR 601.27(b) (biologics) 
Accelerated approval regulations:2   
 
  21 CFR 314.510, Subpart H (drugs) 
  21 CFR 601.41, Subpart E (biologics) 
 
Animal Rule: 3   
 
  21 CFR 314.610(b)(1), Subpart I 
(drugs) 
  21CFR 601.91(b)(1), Subpart H 
(biologics) 
 
Food and Drug Administration Amendments   
Act of 2007 (FDAAA), section 901. 
 
  Section 505(o)(3) of the FD&C Act 
783   
                                                 
1 See the draft guidance for industry How to Comply with the Pediatric Research Equity Act (September 2005).  
When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents. 
 
2 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014). 
 
3 See the guidance for industry Product Development Under the Animal Rule (October 2015). 
22