Department of Health and Human Services 
OFFICE OF 
 
INSPECTOR GENERAL 
 
 
 
 
FDA I M
 IS  SSUING  ORE 
 
 
P
OSTMARKETING 
 
 
R ,
EQUIREMENTS  BUT 
 
 
C
HALLENGES WITH 
 
  O P  
VERSIGHT  ERSIST
 
Suzanne Murrin 
Deputy Inspector General for 
Evaluation and Inspections 
 
July 2016 
OEI-01-14-00390 
   
   
EXECUTIVE SUMMARY:  FDA is Issuing More Postmarketing 
Requirements, but Challenges with Oversight Persist 
OEI-01-14-00390 
 
WHY WE DID THIS STUDY  
 
FDA approves new drugs for sale in the United States through the new drug application 
(NDA) review process.  FDA requires all new drugs to undergo clinical testing to 
demonstrate their safety and efficacy prior to approval.  However, premarket clinical 
trials may not always identify or fully characterize risks.  Postmarketing research can 
provide additional information about the risks, benefits, and optimal use of an approved 
drug.  In 2006, the Office of Inspector General (OIG) found that FDA could not readily 
identify whether or how timely postmarketing studies were progressing toward 
completion, and that FDA lacked an effective monitoring system for postmarketing 
studies.  Since then, the Food and Drug Administration Amendments Act (FDAAA) 
expanded FDAs authority to require postmarketing studies and to take enforcement 
action when sponsors are out of compliance.  This study follows up on OIGs previous 
work in light of FDAs expanded authority. 
 
HOW WE DID THIS STUDY 
 
We analyzed data from FDAs Document Archiving, Reporting, and Regulatory Tracking 
System (DARRTS) for all prescription drug PMRs initiated in FY 2008 through 2014.  
We reviewed all FY 2014 Annual Status Reports (ASRs) and FDA ASR review 
documents for PMRs initiated in our review period. We also reviewed all noncompliance 
communication from FDA to sponsors of PMRs from FY 2008-FY 2014.  Finally, we 
interviewed FDA staff. 
 
WHAT WE FOUND 
 
FDA used its FDAAA authority to issue half of all PMRs in FY 2008 through FY 2014, 
and required multiple types of studies and clinical trials to fulfill PMRs.  It issued PMRs 
for both supplemental applications and NDAs, and the majority of PMRs were related to 
NDAs.  FDA issued PMRs more often for NDAs reviewed through expedited programs 
than for non-expedited NDAs.  Sponsors are completing most PMRs according to 
schedule, but a few PMRs are delayed.  For about half of all PMRs fulfilled in FY 2014, 
FDA required sponsors to make labeling changes and/or take other actions to ensure the 
safety of their drugs.  However, FDA continues to have problems with its data 
management system and work processes, which hinder its ability to track PMRs. 
 
WHAT WE RECOMMEND  
 
FDA should:  
(1) Provide a standardized form for ASRs, ensure that they are complete, and require 
sponsors to submit them electronically.  Standardized forms and electronic submission 
   
   
would provide FDA staff with comparable information across ASRs and eliminate the 
need for manual data entry, enhancing FDAs ability to track PMRs. 
(2)  Build capacity in DARRTS to support PMR oversight.  Automated reports could 
improve FDA staffs ability to identify pending ASR due dates, PMR statuses that are 
overdue for updates, or missing and late ASRs. 
(3)  Determine the reasons why some PMRs have been delayed for years, and take action 
as appropriate. 
 
FDA implemented our recommendation to determine the reasons some PMRs have been 
delayed and concurred with our other two recommendations.   
   
   
 
TABLE OF CONTENTS 
 
Objectives ....................................................................................................1 
Background ..................................................................................................1 
Methodology ................................................................................................6 
Findings........................................................................................................8 
FDA used its FDAAA authority to issue half of all PMRs from FY 
2008 through FY 2014 .....................................................................8 
FDA issued more PMRs NDAs than for supplemental applications 
..........................................................................................................9 
Although a few PMRs are delayed, sponsors are making progress 
toward completing most PMRs according to schedule .................. 11 
For half of all PMRs fulfilled in FY 2014, FDA required sponsors 
to take action, most often related to safety ....................................14 
FDA monitors PMRs, but shortcomings in FDAs data 
management system limit its ability to track PMR progress .........14 
Conclusion and Recommendations ............................................................19 
Agency Comments and Office of Inspector General Response .................21 
Appendix ....................................................................................................22 
Acknowledgments......................................................................................26 
   
   
   
OBJECTIVES 
To determine: 
1.  The extent and nature of postmarketing studies in the context of  the 
Food and Drug Administration (FDA) postmarketing requirements 
(PMR) for certain drugs; 
2.  The extent to which sponsors complete PMRs; 
3.  How and the extent to which FDA oversees PMRs; and 
4.  How and the extent to which FDA takes action based on PMRs. 
BACKGROUND  
FDA approves new drugs for sale in the United States through the new 
drug application review process.  FDA requires that all new drugs undergo 
clinical testing to demonstrate their safety and efficacy prior to approval.  
However, premarket clinical trials may not always identify or fully 
characterize all risks related to the use of a drug.  Postmarketing research 
can provide additional information about the risks, benefits, and optimal 
use of an approved drug.  
Previous work by the Office of Inspector General (OIG) identified 
problems in FDAs monitoring of PMRs.  In 2006 OIG recommended, 
among other things, that FDA improve its information management 
system for monitoring postmarketing studies and ensure that 
postmarketing studies are monitored and annual status reports (ASRs) are 
validated.  FDA agreed to these recommendations and has implemented 
them.1  In 2009, the Government Accountability Office (GAO) similarly 
found that FDA has not routinely met its goal of reviewing status reports 
within 90 days to verify information and the status of postmarketing 
studies.2  More recently, in 2015 GAO found that problems with FDAs 
postmarket study data restrict FDAs ability to perform systematic 
oversight of postmarket drug safety.3 
                        ____________________________________________________________ 
1 Office of Inspector General, FDAs Monitoring of Postmarketing Study Commitments, 
June 2006.  Accessed online: http://oig.hhs.gov/oei/reports/oei-01-04-00390.pdf on 16 
October 2015. 
2 Government Accountability Office, FDA Needs to Enhance its Oversight of Drugs 
Approved on the Basis Use of Surrogate Endpoints, September 2009.  Accessed online: 
http://www.gao.gov/assets/300/295762.pdf on 16 October 2015. 
3 Government Accountability Office, Drug Safety: FDA Expedites Many Applications, 
But Data for Postapproval Oversight Need Improvement, December 2015.  Accessed 
online: http://www.gao.gov/assets/680/674183.pdf on 3 March 2016. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  1   
   
Since OIG last evaluated FDAs oversight of postmarketing research, the 
Food and Drug Administration Amendments Act (FDAAA) expanded 
FDAs authority to require postmarketing studies and to take enforcement 
action against sponsors who fail to comply with the requirements of 
section 505(o)(3) of the Food, Drug and Cosmetic Act (FD&C Act).  
FDAs expanded authority to require postmarketing studies is an important 
tool for assessing serious risk related to the use of a drug.   
Postmarketing Requirements 
Postmarketing studies and clinical trials could measure an approved drugs 
clinical safety, clinical efficacy, clinical pharmacology, or nonclinical 
toxicology.4  FDA may use information from these studies to request an 
update to a drugs label, approve a drug for new uses, require additional 
risk management interventions, or, in rare cases, seek to have the 
manufacturer withdraw a drug from the market.  Likewise, FDA may 
determine that the PMR results indicate that no further action is needed. 
In 2007, Section 901 of the FDAAA amended and added section 505(o) of 
the FD&C Act.  Section 505(o) of the FD&C Act authorizes FDA to 
require postmarket studies or clinical trials involving an approved drug or 
biological product to assess known or potential serious risks related to its 
use.5 Postmarketing studies and clinical trials required by FDA under this 
or other statutory authority are called PMRs.6,7   
Prior to 2007, FDA could only require that applicants conduct 
postmarketing research under the following circumstances: 
  Pediatric Research Equity Act (PREA) PMRs: FDA may approve 
a drug that is ready for approval for use in adults but has not been 
studied in a relevant pediatric population.  In these cases, FDA 
may defer pediatric studies under PREA. 
  Accelerated Approval PMRs: Under the Accelerated Approval 
Pathway, FDA may approve a drug based on a surrogate or 
intermediate clinical endpoint.  These approvals require 
                        ____________________________________________________________ 
4 21 CFR 314.81(b)(2)(vii). 
5 Section 901 of the FDAAA (P.L. 110-85, Sept. 27, 2007) added  505(o)(3) to the 
FFDCA (21 U.S.C.  355(o)(3)). 
6 FDA, Guidance for Industry: Postmarketing Studies and Clinical Trials  
Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act. 
Accessed online: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm172001.pdf on 2 March 2016. 
7 All other postmarketing studies are called postmarketing commitments. Postmarketing 
commitments differ from PMRs because the studies are proposed by FDA, not required.  
An applicant may agree to conduct the studies, and so enters into a commitment with 
FDA.  Our evaluation focused on PMRs. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  2   
   
postmarketing studies or clinical trials to verify the clinical 
benefit.8  
  Animal Efficacy Rule PMRs:  When human clinical trials cannot 
be conducted ethically, FDA may approve a drug based solely on 
animal studies.  In these cases, FDA may require the sponsor to 
conduct postmarketing studies in humans, when feasible and 
ethical.9 
In addition to the authorities listed above, under FDAAA, FDA can 
require one or more PMRs at the time of a drugs approval or after 
approval for one or more of the following reasons: 
  to assess a known serious risk related to the use of the drug,  
  to assess signs of serious risk related to the use of the drug, and/or  
  to identify an unexpected serious risk when available data indicate 
the potential for a serious risk.10 
FDA may issue PMRs related to NDAs or supplemental applications.  A 
sponsor may submit a supplemental application to amend an existing 
approved application.  There are four types of supplemental applications: 
  Efficacy Supplement:  application proposing one or more changes 
to the product labeling, e.g., to add or modify an indication or 
claim, revise the dose, or to significantly alter the intended patient 
population, among other changes.11 
  Labeling Supplement: application proposing labeling changes 
other than those defined by efficacy, manufacturing, and Risk 
Evaluation and Mitigation Strategy (REMS) supplements.12 
  Manufacturing Supplement: application for chemistry, 
manufacturing, and control changes.13 
  REMS Supplement: application proposing a new post-approval 
REMS or a modification of an approved REMS.14 
                        ____________________________________________________________ 
8 Section 506(b)(2)(A) of the FD& C Act; 21 CFR 314.510. 
9 21 CFR  314.610(b)(1). 
10 FDA, Guidance for Industry Postmarketing Studies and Clinical Trials- 
Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act, April 
2011.  Accessed online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM172001.pdf on 16 October 2015. 
11 21 CFR  314.3(b). 
12 21 CFR  314.70. 
13 21 CFR  314.70. 
14 Section 505-1(g) and (h) of the FD&C Act. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  3   
   
Expedited Programs 
Postmarketing research may be particularly useful for applications 
reviewed through expedited programs.  FDA has four expedited programs, 
which are designed to facilitate and expedite development and review of 
new drugs to address an unmet medical need in the treatment of a serious 
condition.15  The four programs are:  
  Accelerated Approval Pathway, 
  Priority Review Designation, 
  Fast Track Designation, and 
  Breakthrough Therapy Designation. 
FDA Procedures for Issuing PMRs 
To issue a PMR, either at the time of approval or after approval, FDA 
notifies the sponsor by letter explaining the purpose and details of the 
required research.  When FDA notifies a sponsor of a PMR, it also 
requests a proposed timetable for completion.  Both FDA and the sponsor 
review and agree on the final timetable for completing each PMR. 
FDA Oversight of PMRs 
Annual Status Reports.  A sponsor must annually report to FDA on the 
status of each open PMR.16  In general, FDA requires annual reports 
(hereinafter referred to as annual status reports, or ASRs), but it may 
require additional reporting on a case-by-case basis.17  FDA and the 
sponsor agree to report due dates as part of the timetable for completing a 
PMR.     
Among other things, these reports must include the status of the PMR.  
Based on a review of the ASR and information submitted by the sponsor, 
FDA assigns each PMR to one of seven status categories: 
  Pending: The study or clinical trial has not been initiated (i.e., no 
subjects have been enrolled or animals dosed), but it does not 
meet the criterion for delayed. 
                        ____________________________________________________________ 
15 FDA, Guidance for Industry: Expedited Programs for Serious Conditions  Drugs and 
Biologics.  Accessed at: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm358301.pdf on 06 January 2015. 
16 Sections 21 CFR 314.81(b)(2)(vii), 505(o)(3)(E)(ii), and section 506B of the FD&C 
Act. 
17 Applicants must submit status reports within 60 days after the anniversary date of the 
applications approval.  FDA, Postmarketing Requirements and Commitments: 
Frequently Asked Questions.  Accessed at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-
marketingPhaseIVCommitments/ucm070766.htm#q8 on 16 October 2015. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  4   
   
  Ongoing:  The study or clinical trial is proceeding according to, 
or ahead of, the original schedule.  FDA considers a PMR to be 
ongoing until a final report is submitted and as long as the PMR 
status is not delayed or terminated. 
  Submitted:  The sponsor has concluded or terminated the study or 
clinical trial and has submitted a final report to FDA, but FDA 
has not yet notified the sponsor that the PMR is fulfilled, not 
fulfilled, or released. 
  Fulfilled:  The sponsor has submitted the final report, and FDA 
has reviewed the report and notified the sponsor in writing that 
the terms of the PMR have been met. 
  Delayed:  The progression of the study or clinical trial is behind 
the original schedule. 
  Terminated:  The sponsor ended the study or clinical trial before 
completion and has not submitted a final report to FDA. 
  Released:  FDA informed the sponsor in writing that it is released 
from its obligation to conduct the study or clinical trial.18  
Administrative and Enforcement Actions.  FDAAA authorizes FDA to take 
actions against sponsors who fail to meet the obligations of a PMR issued 
under section 505(o)(3) of the FD&C Act (hereinafter referred to as 
FDAAA PMRs).  In determining whether to take enforcement action, FDA 
assesses whether a sponsor is out of compliance with the terms of a PMR 
without good cause.  FDA has the discretion to determine good cause.  If a 
sponsor fails to comply with FDAAA PMR requirements without good 
cause, FDA may bring misbranding charges or impose civil monetary 
penalties, among other actions.  FDA typically advises sponsors of 
instances of noncompliance by issuing an untitled letter or warning letter 
prior to pursuing enforcement actions, which allows sponsors an 
opportunity to voluntarily come into compliance.   However, FDA is not 
obligated to provide prior notice through an untitled or warning letter 
before taking an enforcement action. 
FDA may also take action against sponsors who fail to complete a PMR 
under Accelerated Approval, the Animal Efficacy Rule, or PREA.  For a 
drug approved under Accelerated Approval or the Animal Efficacy Rule, 
FDA has the authority to withdraw its approval after appropriate notice 
                        ____________________________________________________________ 
18 FDA, Manual for Policies and Procedures, MAPP 6010.2:  Responsibilities for 
Tracking and Communicating the Status of Postmarketing Requirements and 
Commitments.  Accessed online: 
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProc
edures/UCM174552.pdf on 2 March 2016. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  5   
   
and an opportunity for a hearing if the sponsor fails to conduct a PMR 
with due diligence.  Although FDA may not withdraw the approval of a 
drug if a sponsor fails to submit a pediatric assessment under PREA, this 
failure could result in the drug being considered misbranded and the FDA 
could then initiate an enforcement action. 
Related Work 
As previously noted, in 2006 OIG issued a report titled FDAs Monitoring 
of Postmarketing Study Commitments.  In 2009, GAO released a report 
titled FDA Needs to Enhance its Oversight of Drugs Approved on the 
Basis Use of Surrogate Endpoints, which similarly looked at FDAs 
oversight of postmarketing studies.  In 2015, GAO released a report titled 
Drug Safety: FDA Expedites Many Applications, but Data for 
Postapproval Oversight Need Improvement, which included findings on 
FDAs postmarket study data.  
METHODOLOGY 
Scope 
This study focuses on FDAs PMRs related to NDAs and supplemental 
applications (hereinafter referred to together as applications) for drugs 
approved between FY 2008 and 2014.  This time period coincides with 
FDAs authority to initiate PMRs under FDAAA.   
Our review includes all drug PMRs that FDA issued from 
FY 2008 through 2014.  We excluded postmarketing commitments 
because they are voluntary agreements, not requirements.  For workload 
management purposes, we excluded PMRs for biologic license 
applications and also limited a subset of our analysis to PMRs for 
FY 2014.  We looked at all FY 2014 ASR and FDA ASR review 
documents for PMRs issued in our review period.  We also focused our 
analysis of fulfilled PMRs on those completed in FY 2014.   
Data Collection and Analysis 
We used data from six sources:  
  FDAs Document Archiving, Reporting, and Regulatory Tracking 
System (DARRTS).  FDA uses DARRTS to record PMRs and 
track their status.  DARRTS also contains ASRs.  
  Non-compliance letters including untitled letters and warning 
letters as well as other FDA communications of non-compliance.   
  Fulfilled letters, which are letters that FDA sent to sponsors in FY 
2014 as notification that a PMR is fulfilled. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  6   
   
  Structured interviews with staff in FDAs Center for Drug 
Evaluation and Research. 
  Documents related to FDA review of ASRs. 
  Documents related to actions taken by FDA in response to PMRs. 
Standards 
This study was conducted in accordance with the Quality Standards for 
Inspection and Evaluation issued by the Council of the Inspectors General 
on Integrity and Efficiency. 
   
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  7   
   
FINDINGS 
FDA used its FDAAA authority to issue half of all 
PMRs from FY 2008 through FY 2014 
In this 7-year period, FDA issued 1,256 PMRs for 468 applications.   FDA 
used its FDAAA authority to issue about half (52 percent, or 657) of all 
PMRs in this time period (see table 1).  Prior to FDAAA, FDA could not 
have required these PMRs.  FDAAA authorized FDA to issue PMRs to 
assess a known serious risk related to the use of a drug; to assess a signal 
of a serious risk related to the use of a drug; or to identify an unexpected 
serious risk when available data indicates the potential for a serious risk.  
FDA may issue FDAAA PMRs at the time of approval, or after approval if 
FDA becomes aware of new safety information. 
Table 1:  Authorities Under Which FDA Issued PMRs From FY 2008FY 
2014 
 
PMRs Issued in FY 2008  FY 2014  
Authority Used to Issue PMR  n (Percent of All PMRs) 
FDAAA, n (%)  657 (52%) 
 
Other PMR Authorities, n (%)  599 (48%) 
     PREA  544 
     Accelerated Approval  54  
     Animal Efficacy Rule  1  
Total  1,256 
Source: OIG analysis of FDA DARRTS data, FY 2008FY 2014. 
 
The number of PMRs that FDA issued increased by 111 percent from FY 
2008 to FY 2009, and then remained fairly consistent through FY 2014 
(see table 2).   
Table 2: Total PMRs by Establishment Fiscal Year 
PMR Establishment   
Fiscal Year  All PMRs 
FY 2008  89   
FY 2009  188 
 
FY 2010  168 
FY 2011  194 
 
FY 2012  188 
FY 2013  222   
FY 2014  207 
  Total  1256 
Source: OIG analysis of FDA DARRTS data, FY 2008FY 2014. 
*FDA closed and then, at later dates, re-established five of these PMRs.  OIG used the original PMR establishment 
dates for our analysis. 
 
 
FDA issued the remainder (48 percent, or 599) of PMRs during this time 
under the authorities that existed prior to its FDAAA authority.  FDA 
issued most of these PMRs (43 percent, or 544) under its PREA authority. 
PREA authorizes FDA to issue PMRs for certain drugs that are not 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  8   
   
adequately labeled for use in pediatric populations.  FDA also issued some 
PMRs (4 percent, or 54) under its Accelerated Approval authority and 1 
under its Animal Efficacy Rule authority (see table 2). 
FDA required sponsors to complete various types of postmarketing studies 
and clinical trials to fulfill PMRs.  The research questions that a PMR is 
intended to answer also determine the type of study or clinical trial the 
sponsor conducts.  For example, some questions can be answered with 
studies completed in a laboratory, while other questions require a clinical 
trial.   FDA required many different types of studies:  28 percent (343) of 
the studies in our time period were clinical trials; the remainder of the 
studies conducted during our review time period, 72 percent (876), were 
studies that were not clinical trials, such as observational studies, clinical 
pharmacology studies, and registries of people taking the drug.19 
FDA issued more PMRs for NDAs than for 
Supplemental Applications 
Applications with PMRs represent about 2.5 percent of the 19,029 
applications FDA approved in this 7-year period.  The majority of the 
applications that FDA approved during this time period were supplemental 
applications (97 percent) and the remainder were NDAs (see tables 3 and 
4).  Of the 468 applications with PMRs, just over two-thirds (324) were 
NDAs.  The rest were supplemental applications (144).  FDA issued more 
PMRs related to efficacy supplemental applications than any other type of 
supplemental application (see table 3). 
Table 3: Total Approved Supplemental Applications and Supplemental 
Applications With PMRs by Approval Fiscal Year 
Labeling, 
Manufacturing, 
All  Efficacy  and REMS 
Application  All Approved  Supplemental  Supplemental  Supplemental 
Approval  Supplemental  Applications  Applications  Applications 
Fiscal Year  Applications  with PMRs   With PMRs  With PMRs 
FY 2008  2450  20  13  7 
FY 2009  2536  24  16  8 
FY 2010  2472  25  17  8 
FY 2011  2800  21  18  3 
FY 2012  2869  16  11  5 
FY 2013  2659  13  12  1 
FY 2014  2660  25  14  11 
Total  18446  144  101  43 
Source: OIG analysis of FDA DARRTS Data, FY 20082014. 
                        ____________________________________________________________ 
19 We could not determine the study type for 37 PMRs from FDA DARRTS Data.  
According to FDA, these data were not captured in DARRTS partly because data entry 
staff was unable to easily determine the study type based on the study description in the 
letter establishing the PMR. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  9   
   
Table 4: Total Approved NDAs and NDAs With PMRs by Approval Fiscal 
Year 
Application 
Approval 
Fiscal Year  Total Approved NDAs  NDAs with PMRs  
FY 2008  74  35  
FY 2009  93  57  
FY 2010  72  41  
FY 2011  82  47  
FY 2012  79  41  
FY 2013  89  51  
FY 2014  94  52  
Total  583  324 
Source: OIG analysis of FDA DARRTS Data, FY 20082014 
Furthermore, FDA issued PMRs more often for expedited NDAs than for 
non-expedited NDAs.  Of the 115 expedited NDAs, 73, or 63 percent, had 
PMRs (see table 5). 20  This compares to 51 percent of non-expedited 
NDAs with PMRs.   
FDA may issue more than one PMR for an application; more than half of 
all applications with a PMR had multiple PMRs.  The number of PMRs 
issued per application ranged from 1 to 14. 
Table 5:  Expedited NDAs and Associated PMRs for FY 2008FY 2014 
 
All Approved 
Approval  Expedited (Excluding  Expedited (Excluding 
Fiscal  All Approved  Accelerated  Accelerated Approval) 
Year  NDAs  Approval) NDAs  NDAs with PMRs 
FY 2008  74  12  3  
FY 2009  93  19  13  
FY 2010  72  11  8  
FY 2011  82  19  16  
FY 2012  79  17  9  
FY 2013  89  16  10  
FY 2014  94  21  14  
Total  583  115  73  
Source: OIG Evaluation of FDA DARRTS data, FY 2008FY 2014. 
                        ____________________________________________________________ 
20 For this analysis, expedited NDAs includes those approved drugs that were reviewed 
through breakthrough therapy, fast track, or priority review designation.  We excluded 
applications that were reviewed through the accelerated approval program from this 
analysis because PMRs are always required for approved applications reviewed through 
this pathway.  However, applications may be reviewed through multiple expedited 
programs simultaneously.  Therefore, by excluding accelerated approval applications, we 
have also excluded some applications that were reviewed under other expedited 
programs. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  10   
   
Although a few PMRs are delayed, sponsors are 
making progress toward completing most PMRs 
according to schedule 
FDA determined that the FY 2014 status of most PMRs established from 
FY 2008 through FY 2014 was either pending, ongoing, or fulfilled (see 
table 6).  When FDA issues a PMR, FDA and the sponsor agree to a 
timetable for completion that includes dates by which the sponsor agrees 
to complete study milestones, such as submitting the final study protocol.  
PMRs are likely to be pending, or not expected to have started yet, in the 
year they are issued.  PMR status categories progress from pending to 
ongoing, submitted, and fulfilled.  FDA considers a PMR fulfilled once it 
has reviewed the completed study and notified the sponsor in writing that 
the study meets FDA requirements. 
A PMR could also be delayed, terminated, or released at any point.  PMRs 
may be terminated or released for many reasons.  For example, a sponsor 
may terminate a PMR if it decides to remove the drug from the market.  
FDA may release a PMR if it determines the study is not feasible, if the 
PMR is superseded by another study, if FDA determines the PMR is not 
needed, or if the sponsor withdraws its application to market the drug.  
 Table 6:  FY 2014 Status of PMRs Established FY 2008-FY 2014 
PMRs 
PMR Status Category  n (Percent) 
422 (34%) 
Pending  
260 (21%) 
 Ongoing 
48 (4%) 
Submitted  
291 (23%) 
Fulfilled  
90 (7%) 
Delayed  
5 (0.4%) 
Terminated  
140 (11%) 
Released  
     Not Feasible  55 
     Superseded  49 
     Not Needed  27 
     Not Marketed  9 
Total  1,256  
Source: OIG analysis of FDA DARRTS data, FY 2008FY 2014. 
Note: Percentages do not total 100 due to rounding. 
Seven percent (90) of PMRs were delayed in FY 2014. 
Of those PMRs that FDA categorized as delayed in FY 2014, 32 were 
delayed for 1 year, 34 for 2 years, and 24 for 3 to 5 years (see table 7).  Of 
the 89 PMRs established in FY 2008, 7 were classified as delayed in FY 
2014, 6 years after FDA issued the PMR. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  11   
   
  Table 7: PMRs Delayed in FY 2014 
Number of PMRs Delayed in FY 2014 
Years Delayed  n (Percent)  
1   32 (36%) 
2   34 (38%) 
3   16 (18%) 
4   4 (4%) 
5   4 (4%) 
Total  90 
Source: OIG analysis of FDA DARRTS data, FY 2008-FY 2014. 
According to FDA, sponsors may have good reasons for these delays.  For 
example, a PMR may fall behind schedule because the sponsor and FDA 
have not reached an agreement on the study design or because patient 
enrollment in a clinical trial is taking longer than planned.  For example, 
in one ASR for a PMR involving a clinical trial, the sponsor wrote, 
Clearly, the enrollment is challenging and is behind schedule.   
When a PMR is behind schedule, FDA typically communicates with the 
sponsor to determine the extent and reason for the delay.  In some 
circumstances, FDA may work with the sponsor to establish a revised 
timetable for completion.21  In fact, 30 PMRs that were delayed in FY 
2014 had revised timetables.   
For FDAAA PMRs, FDA determines whether there is a good cause for 
delay.  If the sponsor demonstrates good cause, FDA does not consider the 
sponsor to be out of compliance.  FDA found good cause for delay and 
issued good cause letters for 5 of the 45 FDAAA PMRs that were delayed 
in FY 2014, which indicates that FDA assessed the sponsors explanation 
for the delay, and that FDA determined the sponsor had good cause.22   
FDA ultimately may decide to take action, such as issuing an untitled 
letter or a warning letter, against a sponsor of a delayed FDAAA PMR 
who fails to demonstrate good cause.     
One-third of PMRs established from FY 2008 through FY 2014 
were pending in FY 2014.   
Of the PMRs with pending status in FY 2014, most were established in FY 
2013 or FY 2014 (see Figure 1).  Among the PMRs with pending status in 
FY 2014 were 7 established in FY 2008.  Pending status indicates that the 
PMR study has not started, but that the sponsor has not yet missed the 
milestone due date for submitting the final study protocol.  PMRs are 
                        ____________________________________________________________ 
21 FDA determines the status of a PMR based on the original timetable for completion. 
However, for PREA PMRs, FDA determines the status based on the revised timetable. 
22 We limited our review of good cause letters to those FDA issued in FY 2014.  FDA 
may have made a good cause determination for these PMRs in years prior to FY 2014. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  12   
   
often pending after FDA issues them, for example to allow time for the 
sponsor to design the study and for FDA to review that design.   
PMRs vary in the amount of time it takes for the study to begin (i.e., the 
duration that the PMR is pending).  In our time period, the number of 
years a PMR had pending status ranged from 0 to 7 years, with a median 
of 1 year in pending status.  The variability reflects, among other factors, 
the type of PMR required (e.g., clinical trial or observational study) and 
the anticipated time it will take for the trial or study to start.  FDA staff 
told us that the time it takes for a sponsor to notify it that the trial or study 
began and for FDA staff to update the status may inflate the amount of 
time a PMR is pending. 
Figure 1:  Number of Pending PMRs by Fiscal Year in Which They Were 
Established 
Source: OIG analysis of FDA DARRTS data, FY 2008FY 2014. 
 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  13   
   
For half of all PMRs fulfilled in FY 2014, FDA required 
sponsors to take action, most often related to safety   
FDA may request the sponsor to take action, such as adding safety 
information to a drugs label, based on what it learns from a PMR, or FDA 
may decide that the results of a PMR prove that a signal of risk does not 
indicate a real threat and decide that no further action is needed.  FDA 
required sponsors to take action 61 times in light of information from 58 
of the 108 PMRs fulfilled in 2014 (see table 8). 
 
Table 8:  Actions Requested by FDA Based on the Results of PMRs 
Fulfilled in FY 2014. 
FDA Requested Action  Number 
Requested the sponsor make changes to 
the drugs label regarding safety information  32 
Requested the sponsor make changes to 
the drugs label regarding the drugs 
efficacy  27 
Issued a new PMR  1 
Modified the Sponsors REMS* for the Drug  1 
Total  61 
Source: OIG analysis of FDA data, FY 2014. 
 
*FDA may require a REMS to manage a serious risk associated with a drug
FDA monitors PMRs, but shortcomings in FDAs data 
management system limit its ability to track PMR 
progress 
FDA received 239 FY 2014 ASRs and reviewed 87 percent (209) of 
them.23  FDAs standard is to review ASRs within 90 days of receipt.24  
FDA met that standard for 81 percent (170) of the FY 2014 ASRs it 
reviewed.  DARRTS is the data management system FDA uses to track 
PMRs and the corresponding ASRs, and to identify sponsors that are out 
of compliance with the terms of a PMR, such as the timetable for 
completion.  FDA told us that DARRTS does not automatically generate 
reports of late ASRs, or PMRs with upcoming ASR due dates.  FDA staff 
may independently generate this information, but DARRTS is not 
designed in a way that allows staff to readily identify late or upcoming 
ASRs.  This can hinder FDAs ability to track PMR progress.      
                        ____________________________________________________________ 
23 These ASRs covered approximately 790 PMRs.  We cannot determine the exact 
number because 19 percent of these ASRs lacked PMR identification numbers. 
24 FDA, Guidance for Industry: Reports on the Status of Postmarketing Study 
Commitments  Implementation of 130 of the Food and Drug Administration 
Modernization Act of 1997.  Accessed online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm080569.pdf on 2 March 2016. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  14   
   
FDA sent 32 noncompliance letters to sponsors of PMRs in 
FY 2014.   
These letters correspond to nine of the PMRs that were delayed in FY 
2014 (see table 9).  Not all delayed PMRs resulted in noncompliance 
action.  A sponsor of a delayed PMR may nonetheless be in compliance if, 
for example, the PMR is an FDAAA PMR, and the sponsor has 
demonstrated good cause for delay.25  FDA also may work with sponsors 
to achieve compliance without taking official action.  For example, 
sponsors of delayed PMRs established under non-FDAAA authority may 
provide an explanation sufficient to justify not adhering to the original 
schedule.   
Before FDA can take noncompliance action, it must determine that a 
sponsor of an FDAAA PMR is without good cause, which FDA has the 
discretion to define.26  Good cause applies to FDAAA PMRs, not PMRs 
issued under any other authority (i.e., PREA, Accelerated Approval, or the 
Animal Efficacy Rule). 
Table 9:  PMR Noncompliance Actions FDA Took for PMRs Established 
From FY 2008-FY 2014 
Action  Number of Letters 
Notification of noncompliance with 
PREA letter  22 
Notification of missed PMR milestone 
letter  4 
Failure to demonstrate good cause 
memo  3 
Failure to respond to notification of 
missed PMR milestone letter  1 
Untitled letter  1 
Warning letter  1 
Total  32 
Source: OIG analysis of FDA data, FY 2014.  
Of the 32 noncompliance actions FDA took during this time period, 22 
related to PREA PMRs for which the sponsor either failed to meet 
milestone dates for submitting required information, failed to request a 
deferral extension, or failed to fulfill a PMR.  Of the remaining 
noncompliance actions, eight were related to FDAAA PMRs for which the 
sponsor either failed to meet milestone dates, failed to show good cause, 
or failed to respond to FDA correspondence. 
                        ____________________________________________________________ 
25 For the purposes of this report, noncompliance action refers to the following letters 
and memos: notification of noncompliance with PREA letter, notification of missed PMR 
milestone letter, failure to demonstrate good cause memo, failure to respond to 
notification of missed PMR milestone letter, untitled letter, and warning letter. 
26 As of March 2016 FDA had not released guidance to industry or FDA staff on its 
definition of good cause. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  15   
   
FDA also issued one warning letter related to PMRs established from FY 
2008 through FY 2014.  Prior to issuing that warning letter, FDA sent 
seven written correspondences to the sponsor from May 2010 to February 
2012 in an attempt to resolve questions about a PMR.  The 
correspondence FDA sent include, in the order FDA sent them:  
  two general advice letters requesting clarification and additional 
information, 
  three informal emails following up on FDAs requests,  
  one formal failure to respond letter, and 
  one failure to demonstrate good cause memo.  
FDA issued the warning letter in February 2012, after it determined that 
the sponsor was out of compliance and failed to show good cause.  In the 
warning letter, FDA informed the sponsor that the product was misbranded 
due to the sponsors violation of section 505(o) of the FD&C Act.  The 
final correspondence from FDA is a close-out letter sent 1 year after the 
warning letter and 11 months after the sponsors response to the warning 
letter.  The close-out letter states that FDA determined that the sponsor 
addressed all the violations in the warning letter. 
FDA could not readily locate all FY 2014 ASRs due to 
challenges with ASR format, data management systems, and 
its ASR review process. 
Since our 2006 report in which we identified problems with FDAs 
management system for postmarketing studies and recommended 
improvements, FDA began using DARRTS to track PMRs.  However, that 
system does not fully resolve the challenges FDA faces in tracking PMRs.  
For example, despite OIGs multiple requests and four separate ASR data 
submissions from FDA, OIG cannot independently verify that we received 
ASRs for all open PMRs in FY 2014 because of missing data.27   
The lack of a standard format for ASRs makes it difficult for FDA to track 
PMRs and ASRs and to extract data from ASRs.  For example, some ASRs 
are many pages long and include detailed information, while others are 
just a few sentences.   
In addition to variation in format, ASRs sometimes lacked required 
information.  For example, sponsors did not include PMR identification 
numbers in about 19 percent (46) of the 239 ASRs that covered at least 
                        ____________________________________________________________ 
27 Open PMRs are those with any status other than released or fulfilled. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  16   
   
790 PMRs, and 12 ASRs did not include PMR status.28  FDA relies on this 
basic information to track the progress of PMRs.  OIG issued a similar 
finding in 2006 when a review of ASRs revealed that they lacked required 
elements and information that would be useful in monitoring the progress 
of postmarketing studies.   
Additionally, DARRTS does not automatically produce aggregate reports 
of ASR due dates and submitted ASRs.  According to FDA, DARRTS 
does not track PMRs on the individual PMR-level and does not 
consistently link ASRs to individual PMRs.  Rather, sponsors submit 
ASRs to their application files, and ASRs are tracked by NDA number.  
Although DARRTS does not produce an automated report of ASR due 
dates, FDA staff can take steps to generate that information independently.  
DARRTS also lacks the capability to alert staff when ASRs either are 
approaching a due date or overdue.  These limitations lead FDA tracking 
coordinators to develop their own manual systems for monitoring ASRs.        
The processes for reviewing and recording ASRs present another 
challenge.  Currently sponsors submit ASRs in a format that requires FDA 
to extract and record data manually, rather than uploading the ASR data 
directly to DARRTS.  Sponsors submit ASRs to their application file, and 
then FDA review and project management staff are notified by an 
automated email.  Once review staff have completed their review, FDAs 
data-entry staff are notified by an automated email.  Data entry staff then 
extract the PMR status and other information and record it in DARRTS.  
FDA told us that this process can cause delays in the timely updating of 
PMR status.  
According to FDA, its current ASR review process may also lead to delays 
in status updates and inaccuracies in PMR status data.  For example, we 
identified PMRs with an FY 2014 status of pending, ongoing, delayed, or 
submitted that did not have an updated status in DARRTS for FY 2014.  
We identified 53 out of 825 open PMRs for which FDA last updated the 
status in FY 2012, 7 for which the last update was in FY 2011, and 3 that 
were last updated in FY 2010.  The lack of a status update could indicate 
that FDA did not receive a status update from the sponsor for FY 2014 or 
that FDA received an update but failed to enter the status in its system.  
This raises questions about the accuracy of the PMR status data in 
DARRTS and makes it difficult to track PMR status data by year.     
FDA reported that it is taking steps to improve its system for tracking 
ASRs, including developing automated DARRTS reports of upcoming 
                        ____________________________________________________________ 
28 Because many ASRs lacked PMR identification number, we could not determine the 
exact number of PMRs associated with FY 2014 ASRs.  Analysis of ASRs that did not 
include PMR status was based on FDAs ASR review sheets, of which 31 are missing. 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  17   
   
ASR due dates and overdue ASRs, and providing additional training for 
data entry and report review staff.  FDA also is considering its options for 
improving status report submissions, including whether FDA has the 
authority to require sponsors to submit ASRs electronically. 
  
   
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  18   
   
CONCLUSION AND RECOMMENDATIONS 
PMRs are important in helping FDA further evaluate new drugs.  For 
PMRs to be effective, FDA must be able to fully account for them.  
However, FDAs system for overseeing PMRs is not yet up to the task.   
In 2006, the OIG found problems with FDAs oversight of postmarketing 
studies and made recommendations for improvement.  FDA concurred 
with OIGs recommendations to improve its data management system for 
monitoring postmarketing studies and validating ASRs.  In 2007, FDAAA 
expanded FDAs authority to require PMRs to assess or identify serious 
risks related to the use of a drug.  FDA has taken advantage of its 
expanded authority.  FDA used its FDAAA authority to issue half of all 
PMRs in FY 2008 through FY 2014 and issued at least one PMR for 43 
percent of expedited applications.  FDA also required sponsors to take 
additional actions to improve the safe use of about half of all drugs 
approved in FY 2014 that were required to complete a PMR.  However, 
continued problems with the data management system and work processes 
have hindered FDAs ability to track PMRs.  
Therefore, we recommend that FDA should: 
Provide a standardized form for ASRs, ensure that they are 
complete, and require sponsors to submit them electronically 
Although FDA requires sponsors to include certain information in ASRs, 
format variability and missing information can hinder FDAs ability to 
track ASRs.  By creating a standard form for ASRs and requiring sponsors 
to submit them electronically in a format that eliminates the need for 
manual data entry, FDA staff could have comparable information on each 
ASR and upload ASR data to DARRTS.  FDA should ensure that ASRs 
are complete upon submission, and notify sponsors when ASRs are 
incomplete. These steps should enhance FDAs ability to track PMRs. 
  
Build capacity in DARRTS to support PMR oversight 
Automated reports from DARRTS on the status of ASRs could improve 
FDA staffs ability to identify pending ASR due dates, PMR statuses that 
are overdue for updates, or missing and late ASRs.  To improve the utility 
of DARRTS for overseeing PMRs, FDA could: 
  Add reports to DARRTS for tracking ASRs and PMR statuses, 
  Automate work processes to alert data entry staff that an ASR has 
been reviewed and should be entered into DARRTS, and 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  19   
   
  Conduct routine quality assurance of DARRTS data to ensure 
completeness.  
Determine the reasons that some PMRs have been delayed for 
years, and take action as appropriate 
We found four PMRs that have been delayed for 4 years, and four that 
have been delayed for 5 years.  FDA should review these PMRs and its 
data to determine if they truly are delayed, or only appear to be delayed 
because FDA has not updated their status in DARRTS.  FDA should take 
actions appropriate to resolve these delayed PMRs. 
   
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  20   
   
AGENCY COMMENTS AND OFFICE OF INSPECTOR GENERAL 
RESPONSE 
FDA concurred with two of our recommendations and implemented the 
third.  
FDA concurred with our recommendation regarding a standardized form 
for ASRs, ensuring their completeness, and requiring electronic 
submission.  It stated that it is exploring its options for standardizing the 
ASR form and for requiring sponsors to submit them electronically.  FDA 
also stated that it is revising its policies and procedures to ensure that staff 
are consistently checking that ASRs are complete and following up with 
sponsors to obtain missing information. 
FDA also concurred with our second recommendation to build capacity in 
DARRTS to support PMR oversight.  It has initiated efforts to make 
standard PMR reports available to staff to facilitate the timely updating of 
PMR statuses.  Although FDA has plans for a new informatics system, it 
will make limited upgrades to DARRTS to improve its tracking and 
oversight of PMRs.   
FDA implemented our third recommendation that called for FDA to 
determine the reasons some PMRs had been delayed and to take action as 
appropriate.  Specifically, FDA determined that as of May 13, 2016, only 
one of the PMRs that we asked it to address was still delayed.  FDA has 
been in contact with the sponsor of that delayed PMR and is in the process 
of resolving the delay.   
For the full text of FDAs comments, see the Appendix. 
 
 
 
   
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  21   
   
APPENDIX A 
 
 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  22   
   
 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  23   
   
 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  24   
   
 
 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  25   
   
ACKNOWLEDGMENTS 
This report was prepared under the direction of Joyce Greenleaf, Regional 
Inspector General for Evaluation and Inspections in the Boston regional 
office, and Russell Hereford, Deputy Regional Inspector General.  
Jessica Fargnoli served as the team leader for this study, and Elizabeth 
Havener served as the lead analyst.  Central office staff who provided 
support include Meghan Kearns and Joanne Legomsky. 
 
FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390)  26   
Office of Inspector General
http://oig.hhs.gov  
 
The mission of the Office of Inspector General (OIG), as mandated by Public Law 95452, as  
amended, is  to protect the integrity of the Department of  Health and Human Services  
(HHS) programs, as  well  as the health  and welfare of individuals served by those programs.  
This statutory mission is carried  out through a nationwide network of audits, investigations,  
and inspections conducted by the following operating components: 
Office of Audit Services 
The Office  of  Audit Services  (OAS) provides auditing services  for HHS, either by  conducting  
audits  with its own audit resources or by  overseeing  audit work done by others.  Audits  
examine the performance of HHS programs and/or its grantees and contractors in carrying  
out their respective responsibilities and are intended  to provide independent assessments of 
HHS programs and operations.  These assessments help reduce waste, abuse, and  
mismanagement and promote economy and efficiency  throughout  HHS. 
Office of Evaluation and Inspections 
The Office  of  Evaluation and Inspections (OEI)  conducts national evaluations to  provide 
HHS, Congress, and the public with timely, useful, and reliable information on significant 
issues.  These evaluations focus on preventing fraud,  waste, or abuse  and promoting  
economy, efficiency, and effectiveness of departmental programs.  To promote impact, OEI 
reports also present practical recommendations for improving program operations.  
Office of Investigations 
The Office of Investigations (OI) conducts criminal, civil, and administrative investigations  
of fraud and misconduct  related to HHS programs, operations, and individuals.  With  
investigators working in all 50 States and the District of Columbia, OI  utilizes its resources 
by actively  coordinating with the Department  of Justice  and other Federal, State, and local 
law enforcement authorities.  The investigative efforts of OI often lead to  criminal 
convictions, administrative sanctions,  and/or  civil monetary  penalties.  
Office of Counsel to the Inspector General 
The Office of Counsel to the  Inspector  General (OCIG) provides general legal services to 
OIG, rendering  advice and opinions on HHS programs and operations and  providing all  
legal support for OIGs  internal operations.  OCIG represents  OIG in all civil and 
administrative fraud and  abuse cases involving HHS programs, including False Claims Act, 
program exclusion, and civil monetary penalty cases.  In  connection with these cases, OCIG 
also negotiates and monitors corporate integrity agreements.  OCIG renders advisory 
opinions, issues compliance program  guidance, publishes fraud alerts, and provides other  
guidance  to  the health care industry concerning the anti-kickback statute and other  OIG  
enforcement authorities.