Postmarketing Studies and Clinical 
Trials:  Determining Good Cause 
for Noncompliance with Section 
505(o)(3)(E)(ii) 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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) the Office of New Drugs, 
Immediate Office, Safety Policy Research Initiatives Team at 301-796-0700 (email at 
safetyrequirementsteam@fda.hhs.gov) or (CBER) the Office of Communication, Outreach, and 
Development at 800-835-4709 or 240-402-7800.  
 
 
 
 
 
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) 
 
July 2023 
FDA Amendments Act (FDAAA) 
15030dft.docx 
7/10/2023   
Postmarketing Studies and Clinical 
Trials:  Determining Good Cause 
for Noncompliance with Section 
505(o)(3)(E)(ii) 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  
Center for Biologics Evaluation and Research 
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) 
 
July 2023 
FDA Amendments Act (FDAAA) 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 3 
III.  DETERMINING GOOD CAUSE AND FAILURE TO DEMONSTRATE GOOD 
CAUSE FOR PMR NONCOMPLIANCE ...................................................................... 5 
A.  Determining Good Cause for PMR Noncompliance ................................................................... 5 
B. Examples of PMR Noncompliance FDA Would or Would Not Consider Reasonable Under the 
Circumstances ..................................................................................................................................... 6 
1. Missed Final Protocol Submission Milestone .................................................................................. 6 
2. Missed Study/Clinical Trial Completion Milestone ......................................................................... 7 
3. Missed Final Report Submission Milestone ..................................................................................... 8 
IV.  PROCEDURES ................................................................................................................. 8 
A.  Reporting on the Status of a PMR ................................................................................................ 8 
B.  Submitting an Explanation for PMR Noncompliance or Anticipated Noncompliance ........... 9 
C.  Actions Taken to Correct Circumstances That Led to PMR Noncompliance ......................... 9 
V.  ADVISORY OR ENFORCEMENT ACTION FOR PMR NONCOMPLIANCE ... 10 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Postmarketing Studies and Clinical Trials:  Determining Good 
2  Cause for Noncompliance with Section 505(o)(3)(E)(ii) of the 
3  Federal Food, Drug, and Cosmetic Act 
4  Guidance for Industry1 
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  I.  INTRODUCTION 
17   
18  This guidance provides information for holders of applications for human prescription drugs2 
19  (hereafter applicants) who are required to conduct postmarketing studies or clinical trials under 
20  section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).3  These 
21  postmarketing studies and clinical trials are also commonly referred to as postmarketing 
22  requirements (PMRs), or 505(o)(3) PMRs (hereafter PMRs).  An applicant required to conduct a 
23  PMR under section 505(o)(3) must provide certain information to FDA, including a timetable for 
24  study or clinical trial completion and periodic reports on the status of the study or clinical trial.  
25  If an applicant fails to comply with the timetable or other requirements of section 
26  505(o)(3)(E)(ii), the applicant is in violation of section 505(o)(3), unless the applicant has 
27  demonstrated good cause for its noncompliance or other violation.4 
28   
29  This guidance describes factors FDA considers when determining whether an applicant has 
30  demonstrated good cause for its noncompliance with the timetable for completion of PMR 
31  milestones5 as required under section 505(o)(3).  This guidance also provides information on 
32  relevant procedures including how to communicate with FDA regarding PMR compliance, 
 
1 This guidance has been prepared by a multidisciplinary work group, comprising staff from the Center for Drug 
Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and 
Drug Administration.  
 
2 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. 
 
3 The Food and Drug Administration Amendments Act of 2007 (FDAAA) added section 505(o) to the FD&C Act. 
 
4 Section 505(o)(3)(E)(ii) of the FD&C Act.  
 
5 For purposes of this guidance, milestones 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. 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
33  submission of an explanation of the circumstances that led to noncompliance, and how FDA 
34  notifies an applicant of a determination of noncompliance.  Although this guidance primarily 
35  addresses noncompliance with the timetable for completion of PMR milestones, any violation of 
36  a requirement under section 505(o)(3)(E)(ii) of the FD&C Act is subject to enforcement action, 
37  in the absence of a demonstration of good cause.6 
38   
39  This guidance refers only to PMRs required under section 505(o)(3) of the FD&C Act.  This 
40  guidance does not apply to the following types of PMRs: 
41   
42    Pediatric studies required under section 505B of the FD&C Act (see 21 CFR 314.55(b) 
43  and 601.27(b)). 
44   
45    Trials required as a condition of accelerated approval under section 506(c) of the FD&C 
46  Act and accelerated approval regulations (21 CFR 314.510 and 601.41). 
47   
48    Trials required as a condition of approval based on evidence of effectiveness from 
49  studies in animals under subpart I of 21 CFR 314 (21 CFR 314.610(b)(1)) and subpart H 
50  of 21 CFR 601 (21 CFR 601.91(b)(1)). 
51   
52  This guidance does not apply to nonprescription drugs, including nonprescription drugs that are 
53  approved under a new drug application, or to generic drugs approved under section 505(j) of the 
54  FD&C Act.  Section 505(o) of the FD&C Act applies only to prescription drugs approved under 
55  section 505(b) and biological drug products approved under section 351 of the Public Health 
56  Service Act (PHS Act).7  
57   
58  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
59  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
60  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
61  the word should in Agency guidances means that something is suggested or recommended, but 
62  not required. 
63   
64   
 
6 In addition to a timetable for completion, section 505(o)(3)(E)(ii) of the FD&C Act includes requirements for 
periodic reports on the status of a study required under section 505(o)(3) or otherwise undertaken by the responsible 
person to investigate a safety issue, including whether any difficulties in completing the study have been 
encountered.  Section 505(o)(3)(E)(ii) also includes requirements for periodic reports on the status of clinical trials 
required under section 505(o)(3) or otherwise undertaken by the responsible person to investigate a safety issue, 
including whether enrollment has begun, the number of participants enrolled, the expected completion date, whether 
any difficulties completing the clinical trial have been encountered, and registration information with respect to the 
requirements under section 402(j) of the Public Health Service Act (PHS Act) (42 U.S.C. 282(j)). 
 
7 See section 505(o)(2)(B) of the FD&C Act. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
65  II.  BACKGROUND 
66   
67  Section 505(o)(3) of the FD&C Act authorizes FDA to require certain postmarketing studies and 
68  clinical trials8 for prescription drugs at the time of approval or after approval if FDA becomes 
69  aware of new safety information.9  Section 505(o)(3)(E) requires an applicant to provide certain 
70  information to FDA about its PMR, including a timetable for study or clinical trial completion 
71  and periodic reports on the status of the study or clinical trial.  PMR milestones are in the 
72  timetable to measure the progress of studies and clinical trials.  A timetable with milestone dates 
73  is usually proposed by the applicant, and the FDA review team assesses whether the proposed 
74  timetable will provide for timely completion of the study or clinical trial.  Once milestones are 
75  agreed upon, they are included in the action letter or postapproval letter acknowledging new 
76  PMRs.  This original timetable serves as the basis for determining the status of the PMR,10 even 
77  if the applicant subsequently proposes a revised timetable.11  The milestones generally include, 
78  but are not limited to, the following:  
79   
80  (i)  The final protocol submission date  the date by which the applicant submits a 
81  protocol, the FDA review team has sent comments to the applicant, and the 
82  protocol has been revised and submitted as needed to meet the goal of the study or 
83  clinical trial.12 
84   
85  (ii)  The study or clinical trial completion date  the date the last subject who 
86  enrolled in the study or clinical trial completes the last (per protocol) observation 
87  or evaluation.  
88   
 
8 See the draft guidance for industry Postmarketing Studies and Clinical Trials  Implementation of Section 
505(o)(3) of the Federal Food, Drug, and Cosmetic Act (Revision 1) (October 2019) for FDAs definitions of 
clinical trials and studies for purposes of implementing section 901 of FDAAA.  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.  
 
9 See section 505-1(b)(3) of the FD&C Act for the definition of the term new safety information. See the draft 
guidance for industry Postmarketing Studies and Clinical Trials  Implementation of Section 505(o)(3) of the 
Federal Food, Drug, and Cosmetic Act (Revision 1) for discussion of this term.  When final, this guidance will 
represent the FDAs current thinking on this topic.   
 
10 See 21 CFR 314.81(b)(2)(vii)(a)(8) and the FDAs Postmarketing Requirements and Commitments:  Status and 
Fulfillment Categories web page available at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-
marketingPhaseIVCommitments/ucm070799.htm.  
 
11 21 CFR 314.81(b)(2)(vii)(a)(8) and 601.70(b)(8).  Also, see the guidance for industry Reports on the Status of 
Postmarketing Study Commitments  Implementation of Section 130 of the Food and Drug Administration 
Modernization Act of 1997 (February 2006). 
 
12 The date for this milestone should be selected to allow for the discussion period needed to create a well-designed 
study or clinical trial.  See the draft guidance for industry Postmarketing Studies and Clinical Trials  
Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (Revision 1).  When final, this 
guidance will represent the FDAs current thinking on this topic.   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
89  (iii)  The final report submission date  the date by which the applicant submits a 
90  complete study or clinical trial report to FDA. 
91   
92  A PMR timetable may include additional milestones, including interim milestones.   
93   
94  Section 505(o)(3)(E)(ii) of the FD&C Act requires an applicant to periodically report on the 
95  status of each PMR.13  To comply with section 505(o)(3)(E)(ii), the applicant must also report on 
96  the status of any other study or clinical trial undertaken to investigate a safety issue.  Except 
97  when otherwise provided, FDA considers the submission of the annual report required under 21 
98  CFR 314.81 or 21 CFR 601.70, as applicable, as satisfying this periodic reporting requirement, if 
99  the required elements of information about the status of the PMR set forth in 505(o)(3)(E)(ii) are 
100  included in that report.14   
101   
102  If an applicant fails to meet one or more of the milestones specified in the timetable or fails to 
103  submit periodic reports on the status of the PMR(s), FDA considers the applicant to be in 
104  violation of section 505(o)(3) of the FD&C Act, unless the applicant has demonstrated good 
105  cause for its PMR noncompliance.  Under section 505(o)(3)(E)(ii), FDA is responsible for 
106  determining what constitutes good cause for PMR noncompliance.  FDA makes this 
107  determination by evaluating an applicants explanation of the circumstance(s) that led to the 
108  noncompliance and any other information deemed pertinent.  Violations of requirements under 
109  section 505(o)(3)(E)(ii) are subject to enforcement action, including pursuant to sections 
110  505(o)(1) (charges under section 505 of the FD&C Act), 502(z) (21 U.S.C. 332(z)) (misbranding 
111  charges), and 303(f)(4)(A) (21 U.S.C. 333(f)(4)(A)) (civil monetary penalties).15  Advisory16 and 
 
13 Section 505(o)(3)(E)(ii) also requires that applicants report on the registration information for each clinical trial 
PMR with respect to the requirements under section 402(j) of the PHS Act.  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).  Section 402(j) of the PHS Act requires an applicant to 
submit additional information to the clinical trials data bank (available at https://www.ClinicalTrials.gov) and 
requires drug applications or submissions to include a certification that all applicable requirements have been met.  
An applicant can meet this requirement by submitting FDA Form 3674, which will also satisfy the registration 
information requirement under section 505(o)(3)(E)(ii) of the FD&C Act.    
 
14 With regard to studies, section 505(o)(3)(E)(ii) requires applicants to periodically report on the status of the study, 
including whether any difficulties in completing the study have been encountered.  With regard to clinical trials, 
section 505(o)(3)(E)(ii) requires applicants to periodically report on the status of the trial, including whether 
enrollment has begun, the number of participants enrolled, the expected completion date, and whether any 
difficulties completing the clinical trial have been encountered.  This information is generally included in the annual 
report required under 21 CFR 314.81 or 21 CFR 601.70.  For further information refer to the draft guidance for 
industry Postmarketing Studies and Clinical Trials  Implementation of Section 505(o)(3) of the Federal Food, 
Drug, and Cosmetic Act (Revision 1).  When final, this guidance will represent the FDAs current thinking on this 
topic. 
 
15 In determining the amount of a civil monetary penalty, FDA takes into consideration whether the responsible 
person is making efforts toward correcting the violation. 
 
16 An advisory action communicates the FDAs position on a matter but does not commit FDA to taking 
enforcement action.  FDA considers a warning or untitled letter to be informal and advisory.  An enforcement action 
may include issuance of civil monetary penalties, misbranding charges, and charges under section 505 of the FD&C 
Act.  See sections 303(f)(4)(A) and 502(z) of the FD&C Act.  See the FDAs Regulatory Procedures Manual 
available at https://www.fda.gov/iceci/compliancemanuals/regulatoryproceduresmanual/default.htm.   
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
112  enforcement actions are more fully discussed below (see section V., FDA Action for PMR 
113  Noncompliance).   
114   
115   
116  III.  DETERMINING GOOD CAUSE AND FAILURE TO DEMONSTRATE GOOD 
117  CAUSE FOR PMR NONCOMPLIANCE  
118   
119  A.  Determining Good Cause for PMR Noncompliance 
120   
121  To determine whether an applicant has demonstrated good cause for PMR noncompliance, FDA 
122  evaluates the applicants explanation of the circumstance(s) that led to the noncompliance (i.e., 
123  that caused the noncompliance).  If an applicant fails to provide an explanation for PMR 
124  noncompliance, including lack of response to a direct inquiry from FDA, in general, FDA will 
125  consider the applicant to have failed to demonstrate good cause for the PMR noncompliance. 
126   
127  FDA intends to make a finding of good cause when an applicants explanation for PMR 
128  noncompliance demonstrates that the noncompliance is reasonable under the circumstances.  In 
129  general, FDA considers PMR noncompliance to be reasonable when it results from 
130  circumstances that meet the following criteria: 
131   
132    The circumstance is directly related to the missed milestone;  
133   
134  AND 
135   
136    The circumstance was out of the applicants control; 
137   
138  AND 
139   
140    The circumstance could not have been reasonably anticipated and factored in at the time 
141  the original PMR timetable was finalized.  
142   
143  In determining whether PMR noncompliance is reasonable under the circumstances, FDA may 
144  also consider any other available information that it deems pertinent.   
145   
146  If any one of the aforementioned conditions is not met, in general, FDA will consider the 
147  noncompliance to not be reasonable under the circumstances and the applicant as failing to 
148  demonstrate good cause for the noncompliance. 
149   
150  FDA will notify the applicant in writing of the determination of whether the applicant 
151  demonstrated good cause or failed to demonstrate good cause for PMR noncompliance. 
152   
153  The applicant could be subject to a warning letter followed by enforcement action for PMR 
154  noncompliance.  FDA generally intends to assess the applicants efforts to mitigate or correct the 
155  underlying cause(s) of the PMR noncompliance when considering advisory or enforcement 
156  action (see section V., FDA Action for PMR Noncompliance). 
157   
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
158  B.  Examples of PMR Noncompliance FDA Would or Would Not Consider 
159  Reasonable Under the Circumstances 
160   
161  The following are examples of PMR noncompliance FDA generally would or would not consider 
162  reasonable under the circumstances.  The following examples are for illustrative purposes only 
163  and are not exhaustive: 
164   
165  1.  Missed Final Protocol Submission Milestone 
166   
167  PMR noncompliance associated with failure to submit a final protocol that FDA likely would 
168  find reasonable under the circumstances includes the following: 
169   
170    Submission of a well-organized and complete protocol in advance of the milestone, 
171  followed by delayed FDA concurrence with the protocol resulting in the applicant 
172  missing the deadline for the final protocol submission.  The delay is attributed to causes 
173  within FDA (e.g., ongoing internal scientific deliberations between FDA disciplines 
174  about key protocol issues; delayed communication to the applicant regarding FDAs 
175  recommendations for the final protocol; or changes in regulatory policy since the PMR 
176  was required that prohibit protocol development or initiation, such as substantial revision 
177  of guidance on how to conduct a particular study or clinical trial specified in the original 
178  PMR).  
179   
180    Delay in finalizing a protocol because a particular aspect of the study or clinical trial is 
181  dependent upon the results of a prerequisite investigation for which there are justifiable 
182  delays in initiating or completing the investigation or interpreting the results. For 
183  example, the final protocol submission is delayed: 
184   
185    Because the subsequent clinical trial depends on the results of a dose-finding trial 

186  that is incomplete or  
187   
188    Because an assay that is critical to the design elements of the prerequisite study or 

189  clinical trial is unavailable  
190   
191  PMR noncompliance associated with failure to submit a final protocol that FDA likely would not 
192  find reasonable under the circumstances includes the following: 
193   
194    Delays in manufacturing or launch of the drug, or other reasons for nonavailability of the 
195  drug, that do not affect the applicants ability to write a protocol.  
196   
197    Submission of a proposed protocol that FDA considers unlikely to provide meaningful 
198  data about the safety issues or questions the PMR was intended to address.  
199   
200    Delayed response or lack of response by the applicant to FDA concerns or 
201  recommendations regarding the proposed protocol.  
202   
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
203    Applicants request to FDA to renegotiate the previously issued PMR (e.g., renegotiate 
204  the previously agreed-upon final study or clinical trial design), in the absence of critical 
205  new information making changes necessary. 
206   
207    Applicants assertion that it lacked knowledge of the requirement for a postmarketing 
208  study or clinical trial and/or lack of responsibility for the PMR because the drug 
209  application is now held by a new company that purchased the drug and assumed 
210  responsibility for the application. 
211   
212    Applicants assertion that the study or clinical trial design, as specified in the PMR, 
213  cannot be performed because of resource constraints (for instance, cost, labor, allocation 
214  of resources, or time). 
215   
216  2.  Missed Study/Clinical Trial Completion Milestone 
217   
218  PMR noncompliance associated with failure to complete a study or clinical trial that FDA likely 
219  would find reasonable under the circumstances includes the following: 
220   
221    Significant difficulties that are out of the applicants control and could not have been 
222  anticipated and planned for with regard to subject recruitment for studies or clinical trials, 
223  including, for example, challenges in recruitment of individuals for reasons such as the 
224  following: 
225   
226    Adverse reactions of the drug added to the product labeling and/or the informed 

227  consent document for the study or clinical trial after a PMR was required that make 
228  subject enrollment in a clinical trial of the drug more difficult. 
229   
230    The availability of a new alternative therapy after an applicants PMR was required 

231  that affects usage of the applicants drug. 
232   
233    Unanticipated drug access issues or foreign agency restrictions, such as the following: 
234   
235    Unexpected disruption or interruption in the supply (e.g., drug shortage, drug 

236  discontinuation) of the applicants drug that is out of the applicants control and 
237  delays the conduct of the study or clinical trial. 
238   
239    Drug importation or other unexpected access issues that affect the applicants ability 

240  to obtain a necessary comparator drug for the study or clinical trial. 
241   
242  PMR noncompliance associated with failure to complete a study or clinical trial that FDA likely 
243  would not find reasonable under the circumstances includes the following: 
244   
245    Inadequate subject recruitment for studies or clinical trials for which difficulties in 
246  subject enrollment should be unlikely (e.g., recruitment of healthy subjects for a drug-
247  drug interaction trial or pharmacokinetics trial). 
248   
7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
249    Failure to complete prespecified and feasible interim data analyses that are considered 
250  relevant to inform appropriate completion of the study or clinical trial.    
251   
252  3.  Missed Final Report Submission Milestone 
253   
254  PMR noncompliance associated with failure to submit a final report that FDA would likely find 
255  reasonable under the circumstances includes the following: 
256   
257    Unanticipated drug access issues or foreign agency restrictions that affect the applicants 
258  ability to complete the study or clinical trial and that subsequently interfere with the 
259  applicants ability to submit a final report by the milestone. 
260   
261  PMR noncompliance associated with failure to submit a final report that FDA likely would not 
262  find reasonable under the circumstances includes the following: 
263   
264    Responsible employee(s) have left the applicants firm. 
265   
266    Delayed routine data analysis of completed study or clinical trial results. 
267   
268    Submission of other data in lieu of a final report that the applicant believes will satisfy 
269  the PMR milestone(s) but FDA finds inadequate to address the serious risk that prompted 
270  the PMR. 
271   
272   
273  IV.  PROCEDURES 
274   
275  A.  Reporting on the Status of a PMR 
276   
277  Section 505(o)(3)(E)(ii) of the FD&C Act requires periodic reporting on the status of each study 
278  or clinical trial required under section 505(o)(3), including reporting on whether the applicant 
279  has encountered any difficulties completing the study or clinical trial.  In addition, PMRs 
280  required under section 505(o)(3) are also subject to the reporting requirements of section 506B of 
281  the FD&C Act, as well as 21 CFR 314.81(b)(2)(vii) or 21 CFR 601.70.17  As described in section 
282  II., Background, FDA considers the submission of the annual report required under 21 CFR 
283  314.81(b)(2)(vii) or 21 CFR 601.70, as applicable, containing all of the elements set forth in 
284  505(o)(3)(E)(ii) as satisfying the periodic reporting requirement under section 505(o)(3)(E)(ii).  
285   
 
17 Under these sections of the statute and regulations, applicants are required to submit annual reports on the status 
of any PMR/PMC studies or clinical trials.  These annual reports should include the original milestones, current 
status of the study or clinical trial, an explanation of the progress of the study or clinical trial, any revised 
milestones, and the reasons for the revisions.  See the guidance for industry Reports on the Status of Postmarketing 
Study Commitments  Implementation of Section 130 of the Food and Drug Administration Modernization Act of 
1997 and the draft guidance for industry Postmarketing Studies and Clinical Trials  Implementation of Section 
505(o)(3) of the Federal Food, Drug, and Cosmetic Act (Revision 1).  When final, this guidance will represent the 
FDAs current thinking on this topic. 
8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
286  B.  Submitting an Explanation for PMR Noncompliance or Anticipated 
287  Noncompliance 
288   
289  Because the required milestone may occur far in advance of the required periodic updates that 
290  are generally submitted in an annual report, FDA strongly encourages applicants to proactively 
291  inform FDA about the progress and status of their PMR(s). If an applicant anticipates missing a 
292  milestone or has already missed the milestone and submission of an annual report is not 
293  imminent, FDA encourages the applicant to notify FDA as soon as possible of the delay and 
294  submit thorough explanations of the failure to meet the PMR milestones.  Applicants who have a 
295  revised PMR timetable who fail or anticipate failing to meet any of the revised milestones should 
296  also submit an explanation for FDA to evaluate.  As more fully discussed below, applicants who 
297  miss (or anticipate missing) PMR milestones should promptly implement the appropriate actions 
298  that are necessary to correct the underlying circumstance(s) of the PMR noncompliance and 
299  include a description of these actions in the explanation for PMR noncompliance.   
300   
301  FDA determines whether an applicant has demonstrated good cause for noncompliance with a 
302  PMR milestone in the timetable only after the applicant has missed the milestone date.  FDA 
303  recognizes, however, that an applicant can often know in advance that a milestone may be 
304  missed, proactively notify FDA of the anticipated missed milestone, and provide an explanation 
305  for the anticipated delay.  Before the applicant misses a milestone, FDA can assess whether it 
306  finds that the applicant has provided sufficient justification for the anticipated delay (i.e., 
307  anticipated failure to meet a future milestone).  FDA plans to notify an applicant of its 
308  determination that an applicant has failed to provide sufficient justification for the anticipated 
309  delay in meeting the PMR milestone. 
310   
311  Applicants should identify their submitted explanations for actual or anticipated PMR delay with 
312  the following wording in bold capital letters on the top of the first page of the submission: 
313  Notification of Failure to Meet a PMR Milestone(s) Required Under Section 505(o) or 
314  Notification of Anticipated Failure to Meet a PMR Milestone(s) Required Under Section 
315  505(o). 
316   
317  C.  Actions Taken to Correct Circumstances That Led to PMR Noncompliance 
318   
319  After a missed milestone, or other PMR noncompliance, FDA reviews the explanation provided 
320  to determine whether the applicant has demonstrated that it has undertaken appropriate action to 
321  correct or mitigate the circumstance that led to the PMR noncompliance.  The appropriateness of 
322  these actions depends on the type of milestone and the circumstances underlying the PMR 
323  noncompliance.  However, in general, FDA considers an applicant to have undertaken 
324  appropriate action if the applicant does the following:  
325   
326    Promptly18 develops and implements a reasonable plan to correct the underlying 
327  circumstance(s) leading to the PMR noncompliance; 
328   
 
18 FDA determines an applicants promptness based on the specific circumstance and on a case-by-case basis. 
 
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329    Proactively informs FDA of actual or anticipated delays and the plan to correct the 
330  underlying circumstance(s) leading to the PMR noncompliance; and 
331   
332    Proposes a reasonable revised timetable. 
333   
334  FDA may consider multiple episodes of an applicants failure to meet a PMR milestone in 
335  determining whether the applicant has undertaken appropriate action to correct or mitigate the 
336  circumstance that led to PMR noncompliance.  FDA intends to consider whether the applicant 
337  has taken appropriate actions to correct the circumstances that led to PMR noncompliance when 
338  considering advisory or enforcement action.  
339   
340   
341  V.  ADVISORY OR ENFORCEMENT ACTION FOR PMR NONCOMPLIANCE 
342   
343  Applicants are subject to advisory or enforcement action for any of the following violations of 
344  section 505(o)(3)(E)(ii) of the FD&C Act unless the applicant has demonstrated good cause for 
345  noncompliance: 
346   
347    Failure to meet a milestone in the PMR timetable19  
348   
349    Violation of any other requirement under section 505(o)(3)(E)(ii) of the FD&C Act, 
350  including failure to periodically report on the status of each required postmarketing study 
351  or clinical trial through the submission of a PMR status report in an annual report or by 
352  other means20 
353   
354  Examples of advisory and enforcement actions include the following:  
355   
356    Issuance of a warning or untitled letter.  FDA issues warning letters to applicants to 
357  achieve voluntary compliance before taking enforcement action. An untitled letter cites 
358  violations that do not meet the threshold of regulatory significance for a warning letter.21  
359   
360    Misbranding charges.  A drug is misbranded under section 502(z) of the FD&C Act (21 
361  U.S.C. 352(z)) if the responsible person22 is in violation of postmarketing study or 
362  clinical trial requirements established under section 505(o)(3) of the FD&C Act.  The 
363  introduction or delivery for introduction into interstate commerce of a misbranded 
364  product violates section 301(a) of the FD&C Act.  It is also a prohibited act under section 
 
19 If FDA determines an applicant has demonstrated good cause for missing a milestone in the original PMR 
timetable, FDA will monitor for the applicants compliance with the proposed revised timetable (as acknowledged 
by FDA). 
 
20 21 U.S.C.356b(a) and 21 CFR 314.81(b)(2)(vii) and 601.70(b). 
 
21 See the FDAs Regulatory Procedures Manual available at 
https://www.fda.gov/iceci/compliancemanuals/regulatoryproceduresmanual/default.htm. 
 
22 See section 505(o)(2)(A) of the FD&C Act for a definition of the term responsible person. 
 
10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
365  301(k) of the FD&C Act to do any act with respect to a drug, if such act is done while the 
366  drug is held for sale after shipment in interstate commerce and results in the drug being 
367  misbranded. 
368   
369    Civil monetary penalties, pursuant to section 303(f)(4)(A) of the FD&C Act (21 U.S.C. 
370  333(f)(4)(A)).  Under section 303(f)(4)(A) of the FD&C Act, a responsible person who 
371  violates postmarketing study or clinical trial requirements of section 505(o) of the FD&C 
372  Act shall be subject to a civil monetary penalty of  
373   
374   Not more than $250,000 per violation, and not to exceed $1,000,000 for all such 
375  violations adjudicated in a single proceeding; or  
376   
377   In the case of a violation that continues after FDA provides written notice to the 
378  responsible person, the responsible person shall be subject to a civil monetary penalty 
379  of $250,000 for the first 30-day period (or any portion thereof) that the responsible 
380  person continues to be in violation, and such amount shall double for every 30-day 
381  period thereafter that the violation continues, not to exceed  $1,000,000 for any 30-
382  day period, and not to exceed $10,000,000 for all such violations adjudicated in a 
383  single proceeding.  
384   
385  In determining the amount of a civil penalty, FDA will consider whether the responsible person 
386  is making efforts to correct the violation (see section 303(f)(4)(B) of the FD&C Act).  
387   
388  In general, warning letters for violations of section 505(o)(3) will be posted on FDAs website; 
389  untitled letters may also be posted.23  FDA is not obligated to provide prior notice (e.g., warning 
390  letters) before taking enforcement action. 
 
23 See the FDA Warning Letters and Notice of Violation Letters to Pharmaceutical Companies web page available at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLet
tersandNoticeofViolationLetterstoPharmaceuticalCompanies/ucm594437.htm#OSI.  
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