Department of Health and Human Services

OFFICE OF

INSPECTOR GENERAL

FDA IS ISSUING MORE 

POSTMARKETING 

REQUIREMENTS, BUT 

CHALLENGES WITH 

OVERSIGHT PERSIST

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 FDA’s authority to require postmarketing studies and to take enforcement 

action when sponsors are out of compliance. This study follows up on OIG’s previous 

work in light of FDA’s expanded authority. 

HOW WE DID THIS STUDY 

We analyzed data from FDA’s 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 FDA’s ability to track PMRs.

(2) Build capacity in DARRTS to support PMR oversight. Automated reports could 

improve FDA staff’s 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 FDA’s 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
 

FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390) 1

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 FDA’s 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 FDA’s 

postmarket study data restrict FDA’s ability to perform systematic 

oversight of postmarket drug safety.3

 ____________________________________________________________ 

1 Office of Inspector General, FDA’s 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) 2

Since OIG last evaluated FDA’s oversight of postmarketing research, the 

Food and Drug Administration Amendments Act (FDAAA) expanded 

FDA’s 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). 

FDA’s 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 drug’s 

clinical safety, clinical efficacy, clinical pharmacology, or nonclinical 

toxicology.4

 FDA may use information from these studies to request an 

update to a drug’s 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) 3

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 drug’s 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 TrialsImplementation 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) 4

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 

application’s approval. FDA, Postmarketing Requirements and Commitments: 

Frequently Asked Questions. Accessed at 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PostmarketingPhaseIVCommitments/ucm070766.htm#q8 on 16 October 2015. 
 

FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390) 5

 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) 6

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 FDA’s 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 FDA’s 

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 

FDA’s postmarket study data. 

METHODOLOGY

Scope

This study focuses on FDA’s 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 

FDA’s 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: 

 FDA’s 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) 7

 Structured interviews with staff in FDA’s 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) 8

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 2008–FY 

2014

Authority Used to Issue PMR

PMRs Issued in FY 2008 – FY 2014 

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 2008–FY 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

Source: OIG analysis of FDA DARRTS data, FY 2008–FY 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 

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
 

FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390) 9

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 

Application 

Approval 

Fiscal Year

All Approved 

Supplemental 

Applications

All 

Supplemental 

Applications 

with PMRs 

Efficacy 

Supplemental 

Applications

With PMRs

Labeling, 

Manufacturing, 

and REMS 

Supplemental 

Applications

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 2008–2014. 

 ____________________________________________________________ 

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) 10

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 2008–2014 

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 2008–FY 2014 

Approval 

Fiscal 

Year

All Approved 

NDAs

All Approved 

Expedited (Excluding 

Accelerated 

Approval) NDAs

Expedited (Excluding 

Accelerated Approval) 

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 2008–FY 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) 11

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 

PMR Status Category

PMRs

n (Percent)

Pending 

422 (34%)

Ongoing

260 (21%)

Submitted 

48 (4%)

Fulfilled 

291 (23%)

Delayed 

90 (7%)

Terminated 

5 (0.4%)

Released 

 Not Feasible

 Superseded

 Not Needed

 Not Marketed

140 (11%)

55

49

27

9

Total 1,256 

Source: OIG analysis of FDA DARRTS data, FY 2008–FY 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) 12

 Table 7: PMRs Delayed in FY 2014 

Years Delayed

Number of PMRs Delayed in FY 2014 

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 sponsor’s 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) 13

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 2008–FY 2014. 
 

FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390) 14

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 drug’s 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 drug’s label regarding safety information 32

Requested the sponsor make changes to 

the drug’s label regarding the drug’s 

efficacy 27

Issued a new PMR 1

Modified the Sponsor’s 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 FDA’s data 

management system limit its ability to track PMR 

progress

FDA received 239 FY 2014 ASRs and reviewed 87 percent (209) of 

them.23

 FDA’s 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 FDA’s 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) 15

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) 16

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 FDA’s 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 sponsor’s 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 sponsor’s 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 FDA’s 

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 OIG’s 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) 17

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, FDA’s 

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 FDA’s ASR review sheets, of which 31 are missing.
 

FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390) 18

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) 19

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, FDA’s system for overseeing PMRs is not yet up to the task. 

In 2006, the OIG found problems with FDA’s oversight of postmarketing 

studies and made recommendations for improvement. FDA concurred 

with OIG’s recommendations to improve its data management system for 

monitoring postmarketing studies and validating ASRs. In 2007, FDAAA 

expanded FDA’s 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 FDA’s 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 FDA’s 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 FDA’s ability to track PMRs.

Build capacity in DARRTS to support PMR oversight

Automated reports from DARRTS on the status of ASRs could improve 

FDA staff’s 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) 20

 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) 21

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 FDA’s comments, see the Appendix.
 

FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390) 22

APPENDIX A
 

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
 

FDA is Issuing More Postmarketing Requirements, but Challenges with Oversight Persist (OEI-01-14-00390) 26

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.
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: 

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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 

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HHS programs and operations. These assessments help reduce waste, abuse, and 

mismanagement and promote economy and efficiency throughout HHS. 

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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. 

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The Office of Investigations (OI) conducts criminal, civil, and administrative investigations 

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The Office of Counsel to the Inspector General (OCIG) provides general legal services to 

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