[Federal Register Volume 81, Number 210 (Monday, October 31, 2016)]
[Notices]
[Pages 75411-75419]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-26247]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-N-3083]


Report on the Performance of Drug and Biologics Firms in 
Conducting Postmarketing Requirements and Commitments; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: Under the Federal Food, Drug, and Cosmetic Act (the FD&C Act), 
the Food and Drug Administration (FDA or Agency) is required to report 
annually in the Federal Register on the status of postmarketing 
requirements (PMRs) and postmarketing commitments (PMCs) required of, 
or agreed upon by, holders of approved drug and biological products. 
This notice is the Agency's report on the status of the studies and 
clinical trials that applicants have agreed to, or are required to, 
conduct. A supplemental report entitled ``Supplementary Report: 
Performance of Drug and Biologics Firms in Conducting Postmarketing

[[Page 75412]]

Requirements (PMRs) and Postmarketing Commitments (PMCs) (FY 2013 and 
FY 2014),'' containing additional information and analyses on the 
status of PMRs and PMCs as of September 30, 2013, and September 30, 
2014, is available on FDA's Web site at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/ucm064436.htm.

FOR FURTHER INFORMATION CONTACT: Cathryn C. Lee, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 6484, Silver Spring, MD 20993-0002, 301-
796-0700; or Stephen Ripley, Center for Biologics Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
71, Rm. 3128, Silver Spring, MD 20993-0002, 240-402-7911.

SUPPLEMENTARY INFORMATION: 

I. Background

A. Postmarketing Requirements and Commitments

    A PMR is a study or clinical trial that an applicant is required by 
statute or regulation to conduct postapproval. A PMC is a study or 
clinical trial that an applicant agrees in writing to conduct 
postapproval, but that is not required by statute or regulation. PMRs 
and PMCs can be issued upon approval of a drug \1\ or postapproval, if 
warranted.
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    \1\ For the purposes of this notice, references to ``drugs'' or 
``drug products'' include drugs approved under the FD&C Act and 
biological products licensed under the Public Health Service Act, 
other than biological products that also meet the definition of a 
device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)).
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    FDA can require application holders to conduct postmarketing 
studies and clinical trials:
     To assess a known serious risk, assess signals of serious 
risk, or identify an unexpected serious risk (when available data 
indicates the potential for a serious risk) related to the use of a 
drug product (section 505(o)(3) of the FD&C Act, as added by the Food 
and Drug Administration Amendments Act of 2007 (FDAAA)).
     Under the Pediatric Research Equity Act (PREA), to study 
certain new drugs for pediatric populations, when these drugs are not 
adequately labeled for children. Under section 505B(a)(3) of the FD&C 
Act, the initiation of these studies may be deferred until required 
safety information from other studies in adults has first been 
submitted and reviewed.
     To verify and describe the predicted effect or other 
clinical benefit for drugs approved in accordance with the accelerated 
approval provisions in section 506(c)(2)(A) of the FD&C Act (21 CFR 
314.510 and 601.41).
     For a drug that was approved on the basis of animal 
efficacy data because human efficacy trials are not ethical or feasible 
(21 CFR 314.610(b)(1) and 601.91(b)(1)). PMRs for drug products 
approved under the animal efficacy rule \2\ can be conducted only when 
the drug product is used for its indication and when an exigency (or 
event or need) arises. In the absence of a public health emergency, 
these studies or clinical trials will remain pending indefinitely.
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    \2\ 21 CFR 314.600 for drugs; 21 CFR 601.90 for biological 
products.
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B. Reporting Requirements

    Under the regulations (21 CFR 314.81(b)(2)(vii) and 601.70), 
applicants of approved drugs are required to submit annually a report 
on the status of each clinical safety, clinical efficacy, clinical 
pharmacology, and nonclinical toxicology study or clinical trial either 
required by FDA or that they have committed to conduct, either at the 
time of approval or after approval of their new drug application (NDA), 
abbreviated new drug application (ANDA), or biologics license 
application (BLA). Applicants are required to report to FDA on these 
requirements and commitments made for NDAs and ANDAs under 21 CFR 
314.81(b)(2)(viii), and for BLAs under 21 CFR 601.70(b). The status of 
PMCs concerning chemistry, manufacturing, and production controls and 
the status of other studies or clinical trials conducted on an 
applicant's own initiative are not required to be reported under 21 CFR 
314.81(b)(2)(vii) and 601.70 and are not addressed in this report. 
Furthermore, section 505(o)(3)(E) of the FD&C Act requires that 
applicants report periodically on the status of each required study or 
clinical trial and each study or clinical trial ``otherwise undertaken 
. . . to investigate a safety issue . . . .''
    An applicant must report on the progress of the PMR/PMC on the 
anniversary of the drug product's approval \3\ until the PMR/PMC is 
completed or terminated and FDA determines that the PMR/PMC has been 
fulfilled or that the PMR/PMC is either no longer feasible or would no 
longer provide useful information. The annual status report (ASR) must 
include a description of the PMR/PMC, a schedule for completing the 
PMR/PMC, and a characterization of the current status of the PMR/PMC. 
The report must also provide an explanation of the PMR/PMC status by 
describing briefly the progress of the PMR/PMC. A PMR/PMC schedule is 
expected to include the actual or projected dates for the following: 
(1) Submission of the final protocol to FDA; (2) completion of the 
study or clinical trial; and (3) submission of the final report to FDA.
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    \3\ An applicant must submit an annual status report on the 
progress of each open PMR/PMC within 60 days of the anniversary date 
of U.S. approval of the original application or on an alternate 
reporting date that was granted by FDA in writing. Some applicants 
have requested and been granted by FDA alternate annual reporting 
dates to facilitate harmonized reporting across multiple 
applications.
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C. PMR/PMC Status Categories

    The status of the PMR/PMC must be described in the ASR according to 
the terms and definitions provided in 21 CFR 314.81 and 601.70. For its 
own reporting purposes, FDA has also established terms to describe when 
the conditions of the PMR/PMC have been met, and when it has been 
determined that a PMR/PMC is no longer necessary.\4\ The PMR/PMC status 
categories are summarized in the following list. As reflected in the 
definitions, the status of a PMR/PMC is generally determined based on 
the original schedule.\5\
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    \4\ See the guidance for industry entitled ``Reports on the 
Status of Postmarketing Study Commitments--Implementation of Section 
130 of the Food and Drug Administration Modernization Act of 1997.'' 
We update guidances periodically. To make sure you have the most 
recent version of a guidance, check the FDA Drugs guidance Web page 
at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
    \5\ The definitions for the terms ``pending,'' ``ongoing,'' 
``delayed,'' ``terminated,'' and ``submitted'' are adapted from 21 
CFR 314.81 and 601.70; the definitions for the terms ``fulfilled'' 
and ``released'' are described in the guidance for industry entitled 
``Reports on the Status of Postmarketing Study Commitments--
Implementation of Section 130 of the Food and Drug Administration 
Modernization Act of 1997.''
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     Pending: The study or clinical trial has not been 
initiated (i.e., no subjects have been enrolled or animals dosed), but 
does not meet the criteria for delayed (i.e., the original projected 
date for initiation of subject accrual or initiation of animal dosing 
has not passed).\6\
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    \6\ It is important to note that PMRs/PMCs that are in pending 
status are not yet delayed; that is, per the milestones, the studies 
or clinical trials are indeed on schedule and are not expected to be 
underway yet.
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     Ongoing: The study or clinical trial is proceeding 
according to or ahead of the original schedule.
     Delayed: The study or clinical trial is behind the 
original schedule.\7\
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    \7\ In some instances, an applicant may have justifiable reasons 
for delay of its PMR/PMC (see section I.D).
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     Terminated: The study or clinical trial was ended before 
completion, but

[[Page 75413]]

a final report has not been submitted to FDA.
     Submitted: The study or clinical trial has been completed 
or terminated, and a final report has been submitted to FDA.
     Fulfilled: The final report for the study or clinical 
trial was submitted to FDA and FDA notified the applicant that the 
requirement or commitment was fulfilled through written correspondence.
     Released: FDA has informed the applicant in writing that 
it is released from its obligation to conduct the study or clinical 
trial because the study or clinical trial is no longer feasible, would 
no longer provide useful information, or the underlying application has 
been formally withdrawn.
    In addition to the above statuses, PMRs/PMCs may also be 
characterized as closed or open. ``Open'' PMRs/PMCs comprise those that 
are pending, ongoing, delayed, submitted, or terminated; whereas 
``closed'' \8\ PMRs/PMCs are either fulfilled or released. Open PMRs 
are also described by whether they are on- or off-schedule. ``On-
schedule'' PMRs/PMCs are those that are pending, ongoing, or submitted. 
``Off-schedule'' PMRs/PMCs are those that have missed one of the 
milestone dates in the original schedule and are categorized as either 
delayed or terminated.
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    \8\ Previous FDA reports on the status of PMRs/PMCs used the 
term ``completed'' to refer to PMRs/PMCs that are closed.
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D. Additional Requirements

    If an applicant fails to comply with the original schedule for 
completion of postmarketing studies or clinical trials required under 
section 505(o)(3) of the FD&C Act (i.e., under the FDAAA authorities), 
or fails to submit periodic reports on the status of the studies or 
clinical trials, the applicant is considered to be in violation of 
section 505(o)(3), unless it has demonstrated ``good cause'' for its 
noncompliance or other violation. Failure to meet an original milestone 
and, as a result, falling behind the original schedule is one type of 
noncompliance with a PMR issued under FDAAA. In these circumstances, 
the FDAAA PMR is considered delayed, with or without good cause.
    Section 505B(a)(3)(B) of the FD&C Act, as amended by the Food and 
Drug Administration Safety and Innovation Act, authorizes FDA to grant 
an extension of deferral of pediatric assessments that are required 
under PREA.\9\ On its own initiative or upon request, FDA may grant an 
extension of a pediatric assessment deferral, provided that certain 
applicable PREA criteria for deferral are still met and the applicant 
submits certain materials in support of the extension.\10\ Applicants 
must submit requests for deferral extensions to FDA not less than 90 
days before the date the deferral would otherwise expire. If FDA grants 
the extension of a pediatric study deferral, this new deferral date is 
considered the original due date of the PMR. Consequently, the status 
of PREA PMRs would be determined based on the new deferral date (and 
not the original PREA PMR schedule).
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    \9\ This provision does not apply to PMRs required under other 
provisions, or to PMCs.
    \10\ See section 505B(a)(3)(B) of the FD&C Act.
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    FDA may take enforcement action against applicants who are 
noncompliant with or otherwise fail to conduct studies and clinical 
trials required under FDA statutes and regulations (see, for example, 
sections 505(o)(1), 502(z), and 303(f)(4) of the FD&C Act (21 U.S.C. 
355(o)(1), 352(z), and 333(f)(4))).

II. Understanding FDA's Data on Postmarketing Studies and Clinical 
Trials

A. FDA's Internal PMR/PMC Databases

    Databases containing information on PMRs/PMCs are maintained at the 
Center for Drug Evaluation and Research (CDER) and the Center for 
Biologics Evaluation and Research (CBER). The information in these 
databases is periodically updated as new PMRs/PMCs are issued, upon FDA 
review of PMR/PMC ASRs or other PMR/PMC correspondence, upon receipt of 
final reports from completed studies and clinical trials, and after the 
final reports are reviewed and FDA determines that the PMR/PMC has been 
fulfilled, or when FDA determines that the PMR/PMC is either no longer 
feasible or would no longer provide useful information. Because 
applicants typically report on the status of their PMRs/PMCs annually, 
and because updating the status of PMRs/PMCs in FDA's databases 
involves FDA review of received information, there is an inherent lag 
in updating the data (that is, the data are not ``real time''). FDA 
strives to maintain as accurate information as possible on the status 
of PMRs/PMCs.
    Both CDER and CBER have established policies and procedures to help 
ensure that FDA's data on PMRs/PMCs are current and accurate. When 
identified, data discrepancies are addressed as expeditiously as 
possible and/or are corrected in later reports.
    In 2013, CDER initiated an internal audit of a sample of PMRs and 
PMCs that had been established after March 25, 2008,\11\ to ascertain 
the accuracy of their status. The effort resulted in revisions to the 
status of certain PMRs/PMCs, and procedures to improve tracking and 
accuracy of data on PMRs and PMCs. The details of this audit and 
ensuing activities are summarized in an accompanying supplemental 
report that is available on FDA's Web site at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/ucm064436.htm. CDER's internal audit of its 
PMR/PMC data and subsequent processes for verifying and updating PMR/
PMC status took several months to complete, therefore delaying FDA's 
reporting on PMR/PMC status for fiscal year 2013 (FY2013). As such, 
this report includes CDER and CBER information for both FY2013 and 
fiscal year 2014 (FY2014).
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    \11\ This is the effective date of FDAAA. FDAAA included a new 
requirement for FDA to, among other things, review the entire 
backlog of PMRs and PMCs to determine which ones required revision 
or should be eliminated, and assign start dates and estimated 
completion dates for these PMRs and PMCs. FDAAA also gave new 
authority to require applicants to conduct and report on 
postmarketing studies or clinical trials to assess or identify a 
serious risk related to the use of a drug, and to take action 
against noncompliance with this requirement. Therefore, the 
effective date of FDAAA resulted in certain changes to FDA's 
establishment and monitoring of PMRs and PMCs, and the internal 
audit was intended to evaluate data for a sample of the PMRs and 
PMCs that had been established after FDAAA took effect.
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B. Publicly Available PMR/PMC Data

    FDA also maintains an online searchable and downloadable database 
that contains information about PMRs/PMCs that is publicly reportable 
(i.e., for which applicants must report on the status of the study or 
clinical trial, as required under section 506B of the FD&C Act). The 
data are a subset of all PMRs/PMCs and reflect only those postmarketing 
studies and clinical trials that, at the time of data retrieval, either 
had an open status or were closed within the past year. Information on 
PMRs/PMCs closed more than a year before the date the data are 
extracted (i.e., September 30 of the reporting fiscal year) are not 
included on the public Web site. The FDA Web site is updated 
quarterly.\12\ The FDA Web site does not include information about PMCs 
concerning chemistry, manufacturing, and controls. It is FDA policy not 
to post information on the Web site until

[[Page 75414]]

it has been verified and reviewed for suitability for public 
disclosure.
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    \12\ http://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm
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III. About This Report

    This report is published to fulfill the annual reporting 
requirement under section 506B(c) of the FD&C Act. Information in this 
report covers any PMR/PMC that was made, in writing, at the time of 
approval or after approval of an application or a supplement to an 
application (see section I.A) and summarizes the status of PMRs/PMCs in 
FY2013 (i.e., as of September 30, 2013) and FY2014 (i.e., as of 
September 30, 2014). The information in this report reflects the PMR/
PMC status in CBER's and CDER's databases at the time the data were 
extracted (September 30 of the fiscal year). Specifically, the report 
summarizes the status of all open PMRs/PMCs at the end of the fiscal 
year, and the status of only those PMRs/PMCs that were closed in the 
fiscal year. If a requirement or commitment did not have a schedule, or 
an ASR was not received in the previous 12 months, the PMR/PMC is 
categorized according to the most recent information available to the 
Agency.\13\
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    \13\ Although the data included in this report do not include a 
summary of reports that applicants have failed to file by their due 
date, the Agency notes that their inclusion or description in this 
report has no effect on the Agency's ability to take appropriate 
regulatory action in the event reports are not filed on a timely 
basis.
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    This report reflects combined data from CDER and CBER. Information 
summarized in the report includes the following: (1) The number of 
applicants with open PMRs/PMCs \14\; (2) the number of open PMRs/PMCs; 
(3) the number of applications for which an ASR was expected but was 
not submitted within 60 days of the anniversary date of U.S. approval 
or an alternate reporting date that was granted by FDA; (4) FDA-
verified status of open PMRs/PMCs reported in 21 CFR 314.81(b)(2)(vii) 
or 601.70 ASRs; (5) the status of closed PMRs/PMCs; and (6) the 
distribution of the status by fiscal year of establishment \15\ (fiscal 
year 2008 (FY2008) to FY2014) for PMRs and PMCs that were open at the 
end of FY2014 or closed within FY2014. The tables in this report 
distinguish between PMRs and PMCs, PMRs/PMCs for NDAs and BLAs,\16\ and 
on-schedule and off-schedule PMRs/PMCs, according to the original 
schedule milestones. A more detailed summary of this information and 
additional information about PMRs/PMCs is provided on FDA's Web site at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm. In the accompanying 
supplemental report, information is presented separately for CDER and 
CBER.
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    \14\ At the end of FY2013 and FY2014, there were no PMRs/PMCs 
for ANDAs that met the reporting requirements under FDAMA. 
Therefore, this report reflects information for NDAs and BLAs only.
    \15\ The establishment date is the date of the formal FDA 
communication to the applicant that included the final FDA required 
(PMR), or requested (PMC), postmarketing study or clinical trial.
    \16\ Before July 2014, all BLA PMR/PMC data were maintained in 
CBER's data system. In July 2014, the data for CDER-managed BLAs 
were migrated to CDER's data system. Similar to previous reports, 
this report presents data for CDER and CBER BLAs combined.
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    Numbers published in this report and in the accompanying 
supplemental report on FDA's Web site cannot be compared with the 
numbers resulting from searches of the publicly accessible and 
downloadable database. This is because this report incorporates data 
for all PMRs/PMCs in FDA databases as of the end of the fiscal year, 
including PMRs/PMCs undergoing review for accuracy. The publicly 
accessible and downloadable database includes a subset of PMRs/PMCs, 
specifically those that, at the time of data retrieval, either had an 
open status or were closed within the past 12 months. In addition, the 
status information in this report is updated annually while the 
downloadable database is updated quarterly (i.e., in January, April, 
July, and October).

IV. Summary of Information on PMR/PMC Status

    This report provides information on PMRs/PMCs as of September 30, 
2013 (i.e., for FY2013) and September 30, 2014 (i.e., for FY2014). It 
is important to note that a comparison of the number of open and on-
schedule or off-schedule PMRs/PMCs over time can be misleading because 
it does not take into account that the cohort of open PMRs/PMCs is not 
static from year to year. New PMRs/PMCs are continually being 
established for studies and clinical trials with varying start dates 
and durations; and other PMRs/PMCs are closed because they are either 
fulfilled or released. Also, ongoing PMRs/PMCs are carried forward into 
the subsequent fiscal year. Therefore, the number of on- and off-
schedule PMRs/PMCs can vary from year to year, and a year-to-year 
comparison of on- or off-schedule PMRs/PMCs (e.g., to assess for a 
potential trend) is not appropriate.
    Although a comparison of the number of open and on-schedule or off-
schedule PMRs/PMCs over time is not appropriate for the aforementioned 
reasons, a comparison of the data for FY2013 and FY2014 may be helpful 
in understanding the effect of CDER's 2013 audit. The observed 
differences are considered to reflect the results of CDER's efforts to 
update the information on the statuses of PMRs and PMCs following the 
internal audit of the data for a sample of PMRs/PMCs (see section 
II.A), as well as the natural progress of postmarketing studies and 
clinical trials over time. Finally, due to rounding, the percentages in 
the tables may not add up to 100 percent.

A. Applicants With Open PMRs/PMCs

    An applicant may have multiple approved drug products, and an 
approved drug product may have multiple PMRs and/or PMCs. Table 1 shows 
that as of September 30, 2013, there were 256 unique applicants with 
open PMRs/PMCs under 613 unique NDAs and BLAs. There were 184 unique 
NDA applicants (and 496 associated applications) and 72 unique BLA 
applicants (and 117 associated applications) with open PMRs/PMCs.
    As of September 30, 2014, there were 257 unique applicants with 
open PMRs/PMCs under 639 unique NDAs and BLAs. There were 181 unique 
NDA applicants (and 510 associated applications) and 76 unique BLA 
applicants (and 129 associated applications) with open PMRs/PMCs.

B. Annual Status Reports Received

    As previously mentioned, applicants must submit an ASR on the 
progress of each open PMR/PMC within 60 days of the anniversary date of 
U.S. approval of the original application or an alternate reporting 
date that was granted by FDA (21 CFR 314.81 and 21 CFR 601.70).\17\ 
Table 2 shows that there were 530 NDAs and BLAs with an ASR due in 
FY2013 (429 NDAs and 101 BLAs).\18\ Of the NDA ASRs due in that fiscal 
year, 60 percent (257/429) were received on time, 21 percent (90/429) 
were not received on time, and 19 percent (82/429) were not received 
during FY2013. There were 101 BLAs with an ASR due

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in FY2013. Of the BLA ASRs due, 69 percent (70/101) were received on 
time, 20 percent (20/101) were not received on time, and 11 percent 
(11/101) were not received during FY2013.
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    \17\ An applicant must submit an ASR on the progress of each 
open PMR/PMC within 60 days of the anniversary date of U.S. approval 
of the original application or on an alternate reporting date that 
was granted by FDA in writing. Some applicants have requested and 
been granted by FDA alternate annual reporting dates to facilitate 
harmonized reporting across multiple applications.
    \18\ The number of ASRs that were expected is different from the 
total number of unique applications with open PMRs/PMCs because not 
all applications had an ASR due during FY2013/FY2014. Applicants 
with PMRs/PMCs associated with multiple applications may have 
submitted the ASR to only one of the applications. In addition, if 
all of the PMRs/PMCs for an application were established in the 
preceding fiscal year, or if all PMRs/PMCs for an application were 
closed before the ASR due date, submission of an ASR would not have 
been expected.
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    There were 569 NDAs and BLAs with an ASR due in FY2014 (454 NDAs 
and 115 BLAs). Of the 454 NDA ASRs due in that fiscal year, 58 percent 
(265/454) were received on time, 19 percent (88/454) were not received 
on time, and 22 percent (101/454) were not received during FY2014. Of 
the 115 BLA ASRs due, 63 percent (73/115) were received on time, 19 
percent (20/115) were not received on time, and 19 percent (22/115) 
were not received during FY2014.

C. Overview of On- and Off-Schedule Open PMRs/PMCs

    Table 3 shows that as of September 30, 2013, most open PMRs (84 
percent for NDAs and 89 percent for BLAs) and most open PMCs (77 
percent for NDAs and 74 percent for BLAs) were progressing on schedule 
(i.e., were not delayed or terminated). Similarly, as of September 30, 
2014, most open PMRs (87 percent for NDAs and 88 percent for BLAs) and 
most open PMCs (68 percent for NDAs and 77 percent for BLAs) were 
progressing on schedule.

D. Open and On-Schedule PMRs

    Table 4 shows that as of September 30, 2013, the majority of open 
NDA PMRs (60 percent; 534/887) and open BLA PMRs (45 percent; 80/179) 
were pending.\19\ This is similar to the findings from fiscal year 
2012.\20\ As of September 30, 2014, 48 percent (456/943) of open NDA 
PMRs and 38 percent (74/194) of open BLA PMRs were pending. Table 4 
also shows that the proportion of open NDA PMRs that were categorized 
as ongoing increased from 19 percent (166/887) at the end of FY2013 to 
32 percent (303/943) at the end of FY2014.
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    \19\ It is important to note that PMRs/PMCs that are in pending 
status are not yet delayed; that is, per the milestones, the 
studies/clinical trials are indeed on schedule and are not expected 
to be underway yet.
    \20\ As of September 30, 2012, 58 percent of open NDA PMRs and 
46 percent of open BLA PMRs were pending (79 FR 9230, February 18, 
2014).
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    Table 4 also shows that the proportion of open BLA PMRs that were 
pending decreased between FY2013 (45 percent; 80/179) and FY2014 (38 
percent; 74/194). The proportion of open BLA PMRs that were ongoing did 
not change substantially between FY2013 (32 percent; 57/179) and FY2014 
(35 percent; 68/194).
    In addition, table 4 provides detail on the status of open PMRs and 
PMCs for each category of PMR. The table shows that as of September 30, 
2013, 50 percent (305/614) of pending PMRs for drug and biological 
products were in response to the requirements under PREA. The next 
largest category of pending PMRs for drug and biological products (47 
percent; 286/614) comprises those studies/clinical trials required by 
FDA under FDAAA. As of September 30, 2014, PREA PMRs and FDAAA PMRs 
comprised 55 percent (292/530) and 42 percent (222/530) of pending 
PMRs, respectively.

E. Open and Off-Schedule PMRs

    Table 5 provides additional information on the status of open and 
off-schedule (i.e., delayed and terminated) PMRs. At the end of FY2013, 
16 percent (143/887) of the open NDA PMRs and 11 percent (20/179) of 
the open BLA PMRs were off-schedule. The majority of the off-schedule 
NDA PMRs (98 percent; 140/143) were delayed; the remaining 2 percent 
(3/143) were terminated. At the end of that same fiscal year, 10 
percent (18/179) of the open BLA PMRs were delayed and 1 percent (2/
179) were terminated. Most of the off-schedule BLA PMRs (90 percent; 
18/20) were delayed.
    As of September 30, 2014, 13 percent (126/943) of the open NDA PMRs 
were off-schedule. Of the off-schedule NDA PMRs, 94 percent (118/126) 
were off-schedule because they were delayed and the remaining 6 percent 
(8/126) were terminated. At the end of FY2014, 12 percent (24/194) of 
the open BLA PMRs were off-schedule. The majority of the off-schedule 
BLA PMRs (88 percent; 21/24) were off-schedule because they were 
delayed; the remaining 2 percent (3/194) were terminated.
    In certain situations, the original PMR schedules were adjusted for 
unanticipated delays in the progress of the study or clinical trial 
(e.g., difficulties with subject enrollment in a clinical trial for a 
marketed drug or need for additional time to analyze results). In this 
report, study or clinical trial status reflects the status in relation 
to the original \21\ study or clinical trial schedule regardless of 
whether FDA has acknowledged that additional time was required to 
complete the study or clinical trial.
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    \21\ With the exception of PREA PMRs for which a deferral 
extension of the final report submission date has been granted.
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F. Open On-Schedule and Off-Schedule PMCs

    Table 6 provides the status of open on-schedule and off-schedule 
PMCs. As shown in the table, pending NDA PMCs comprised the largest 
category of all open NDA PMCs as of September 30, 2013 (37 percent; 97/
264), and September 30, 2014 (29 percent; 61/207). Among all open BLA 
PMCs, 35 percent (88/251) and 30 percent (69/228) were pending at the 
end of FY2013 and FY2014, respectively.
    As of September 30, 2013, the largest category of off-schedule PMCs 
were delayed according to the original schedule milestones.\22\ 
Similarly, as of September 30, 2014, the majority of off-schedule NDA 
and BLA PMCs were delayed according to the original schedule 
milestones.\23\
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    \22\ As of September 30, 2013, off-schedule PMCs accounted for 
23 percent (61/264) of open NDA PMCs and 26 percent (65/251) of open 
BLA PMCs.
    \23\ As of September 30, 2014, off-schedule PMCs accounted for 
32 percent (66/207) of open NDA PMCs and 23 percent (53/228) of open 
BLA PMCs.
---------------------------------------------------------------------------

G. Closed PMRs and PMCs

    Table 7 provides details about PMRs and PMCs that were closed 
(released or fulfilled) within FY2013 and FY2014. The majority of 
closed PMRs were fulfilled (53 percent of NDA PMRs and 88 percent of 
BLA PMRs at the end of FY2013; 72 percent of NDA PMRs and 77 percent of 
BLA PMRs at the end of FY2014). Similarly, the majority of PMCs closed 
within FY2013 and FY2014 were fulfilled.

H. Distribution of the Status of PMRs and PMCs

    Tables 8 and 9 show the distribution of the statuses of PMRs/PMCs 
as of September 30, 2014, of all PMRs and PMCs, presented by the year 
that the PMR/PMC was established (FY2008 to FY2014).\24\ Note that the 
data shown for closed (fulfilled or released) PMRs/PMCs is for all 
PMRs/PMCs that were closed as of FY2014. Therefore, data for PMRs/PMCs 
that were closed in prior fiscal years are included. Based on the data 
shown in table 8, an average of 243 PMRs were established each year 
since fiscal year 2009.25 26 Most PMRs that were established 
in the earlier years

[[Page 75416]]

were either fulfilled or released. For example, as of September 30, 
2014, 45 percent (57/128) of the PMRs that were established in FY2008 
were fulfilled, and 22 percent (28/128) were released. The majority of 
PMRs that were established in more recent years were either pending 
(i.e., not yet underway) or ongoing (i.e., still in progress and on 
schedule). For example, as of September 30, 2014, 87 percent (226/260) 
of the PMRs established in FY2014 were pending, and 9 percent (23/260) 
were ongoing. Overall, of the PMRs that were pending as of September 
30, 2014, 81 percent (414/512) were created within the past 3 years. 
Finally, table 8 shows that, on average, 7 percent of the PMRs 
established since FY2008 were delayed (as of September 30, 2014). Table 
9 provides an overview of PMCs in a similar manner as table 8 does for 
PMRs and shows similar results for PMCs as those for PMRs as described 
above and in table 8.
---------------------------------------------------------------------------

    \24\ The establishment date is the date of the formal FDA 
communication to the applicant that included the final FDA required 
(PMR) or requested (PMC) postmarketing study or clinical trial.
    \25\ The number of PMRs issued at any particular period is 
determined by a variety of factors including but not necessarily 
limited to: (1) The number of NDAs approved in that period; (2) 
whether additional efficacy or clinical benefit issues were 
evaluated; (3) if any drug-associated serious risk(s) have been 
identified; and (4) whether or not FDA determines that a 
postmarketing study or clinical trial is necessary to further assess 
risk(s) or efficacy issues.
    \26\ Data for FY2008 were not included in the calculation of the 
average number of PMRs established each year because, given that 
FDAAA took effect on March 25, 2008, data are only available for a 
partial fiscal year.

       Table 1--Applicants and Applications (NDA/BLA) With Open Postmarketing Requirements and Commitments
                           [Numbers as of September 30, 2013, and September 30, 2014]
----------------------------------------------------------------------------------------------------------------
                                                                                                 Total (NDA and
                           FY 2013                                 NDA \1\         BLA \2\            BLA)
----------------------------------------------------------------------------------------------------------------
Number of unique applicants with open PMRs/PMCs..............             184              72                256
Number of applications with open PMRs/PMCs...................             496             117                613
----------------------------------------------------------------------------------------------------------------
FY 2014                                                               NDA \1\         BLA \2\              Total
                                                                                                   (NDA and BLA)
----------------------------------------------------------------------------------------------------------------
Number of unique applicants with open PMRs/PMCs..............             181              76                257
Number of applications with open PMRs/PMCs...................             510             129                639
----------------------------------------------------------------------------------------------------------------
\1\ Includes two NDAs with associated PMRs/PMCs managed by CBER.
\2\ Includes BLAs managed by both CDER and CBER.


                                     Table 2--Annual Status Reports Received
                         [Numbers as of September 30, 2013, and September 30, 2014] \1\
----------------------------------------------------------------------------------------------------------------
                                                         Received, on time   Received, not on   Expected but not
                                          Expected \2\       \3\ (% of        time \4\ (% of     received (% of
                                                             expected)          expected)          expected)
----------------------------------------------------------------------------------------------------------------
FY 2013:
  NDA..................................             429          257 (60%)           90 (21%)           82 (19%)
  BLA..................................             101           70 (69%)           20 (20%)           11 (11%)
FY 2014:
  NDA..................................             454          265 (58%)           88 (19%)          101 (22%)
  BLA..................................             115           73 (63%)           20 (19%)           22 (19%)
----------------------------------------------------------------------------------------------------------------
\1\ Percentages may not total 100 due to rounding.
\2\ ASR expected during fiscal year (within 60 days (before or after) of the anniversary of original approval
  date or alternate agreed-upon date).
\3\ ASR was received within 60 days (before or after) of the anniversary of the original approval date or
  alternate agreed-upon date.
\4\ ASR was received, but not within 60 days (before or after) of the anniversary of the original approval date
  or alternate agreed-upon date.


               Table 3--Summary of On- and Off-Schedule Postmarketing Requirements and Commitments
                         [Numbers as of September 30, 2013, and September 30, 2014] \1\
----------------------------------------------------------------------------------------------------------------
                                                        Open PMRs N = 1,066              Open PMCs N = 515
                                                 ---------------------------------------------------------------
                     FY 2013                      NDA (% of Open  BLA (% of Open  NDA (% of Open  BLA (% of Open
                                                     NDA PMRs)       BLA PMRs)       NDA PMCs)       BLA PMCs)
----------------------------------------------------------------------------------------------------------------
On-schedule.....................................       744 (84%)       159 (89%)       203 (77%)       186 (74%)
Off-schedule....................................       143 (16%)        20 (11%)        61 (23%)        65 (26%)
                                                 ---------------------------------------------------------------
    Total.......................................             887             179             264             251
----------------------------------------------------------------------------------------------------------------
                                                             Open PMRs
                                                             Open PMCs
FY 2014                                                      N = 1,137
                                                              N = 435
                                                 ---------------------------------------------------------------
                                                             NDA             BLA             NDA             BLA
                                                  (% of Open NDA  (% of Open BLA  (% of Open NDA  (% of Open BLA
                                                           PMRs)           PMRs)           PMCs)           PMCs)
----------------------------------------------------------------------------------------------------------------
On-schedule.....................................       817 (87%)       170 (88%)       141 (68%)       175 (77%)
Off-schedule....................................       126 (13%)        24 (12%)        66 (32%)        53 (23%)
                                                 ---------------------------------------------------------------
    Total.......................................             943             194             207             228
----------------------------------------------------------------------------------------------------------------
\1\ Percentages may not total 100 due to rounding.


[[Page 75417]]


                                           Table 4--Summary of Open and On-Schedule Postmarketing Requirements
                                             [Numbers as of September 30, 2013, and September 30, 2014] \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                         FY 2013                              NDA N = 887 (% of Total open NDA PMRs)          BLA N = 179 (% of Total open BLA PMRs)
--------------------------------------------------------------------------------------------------------------------------------------------------------
             Reporting authority/PMR status                   Pending         Ongoing        Submitted        Pending         Ongoing        Submitted
--------------------------------------------------------------------------------------------------------------------------------------------------------
Accelerated approval....................................         17 (2%)         12 (1%)         1 (<1%)         1 (<1%)          8 (4%)               0
PREA \2\................................................       272 (31%)         65 (7%)         10 (1%)        33 (18%)         13 (7%)          4 (2%)
Animal efficacy \3\.....................................         2 (<1%)               0               0          3 (2%)               0               0
FDAAA safety (since March 25, 2008).....................   \4\ 243 (27%)        89 (10%)     \5\ 33 (4%)        43 (24%)        36 (20%)        18 (10%)
                                                         -----------------------------------------------------------------------------------------------
    Total...............................................       534 (60%)       166 (19%)         44 (5%)        80 (45%)        57 (32%)        22 (12%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                NDA
                                                                                BLA
FY 2014                                                                       N = 943
                                                                              N = 194
                                                                    (% of Total open NDA PMRs)
                                                                    (% of Total open BLA PMRs)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Reporting authority/PMR status                                   Pending         Ongoing       Submitted         Pending         Ongoing       Submitted
--------------------------------------------------------------------------------------------------------------------------------------------------------
Accelerated approval....................................         8 (<1%)         26 (3%)               0          3 (2%)          4 (2%)          2 (1%)
PREA....................................................       253 (27%)       136 (14%)         27 (3%)        39 (20%)        20 (10%)          8 (4%)
Animal efficacy.........................................         2 (<1%)               0         1 (<1%)          3 (2%)               0               0
FDAAA safety (since March 25, 2008).....................   \6\ 193 (20%)       141 (15%)         30 (3%)        29 (15%)        44 (23%)         18 (9%)
                                                         -----------------------------------------------------------------------------------------------
    Total...............................................       456 (48%)       303 (32%)         58 (6%)        74 (38%)        68 (35%)        28 (14%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Percentages may not total 100 due to rounding.
\2\ Many PREA studies have a pending status. PREA studies are usually deferred because the drug product is ready for approval in adults. Initiation of
  these studies may be deferred until additional safety information from other studies has first been submitted and reviewed before beginning the
  studies in pediatric populations.
\3\ PMRs for drug products approved under the animal efficacy rule (21 CFR 314.600 for drugs; 21 CFR 601.90 for biological products) can be conducted
  only when the drug product is used for its indication and when an exigency (or event or need) arises. In the absence of a public health emergency,
  these studies or clinical trials will remain pending indefinitely.
\4\ Includes one NDA PMR FDAAA safety study from CBER in pending status.
\5\ Includes one NDA PMR FDAAA safety study from CBER in submitted status.
\6\ Includes one NDA PMR FDAAA safety study from CBER in pending status.


                      Table 5--Summary of Open and Off-Schedule Postmarketing Requirements
                         [Numbers as of September 30, 2013, and September 30, 2014] \1\
----------------------------------------------------------------------------------------------------------------
                     FY2013                         NDA N = 887 (% of Open NDA      BLA N = 179 (% of Open BLA
-------------------------------------------------              PMRs)                           PMRs)
                                                 ---------------------------------------------------------------
         Reporting authority/PMR status               Delayed       Terminated        Delayed       Terminated
----------------------------------------------------------------------------------------------------------------
Accelerated approval............................        7 (0.8%)        1 (0.1%)        1 (0.6%)               0
PREA............................................        94 (11%)        2 (0.2%)          6 (3%)          2 (1%)
Animal efficacy.................................        1 (0.1%)               0               0               0
FDAAA safety (since March 25, 2008).............         38 (4%)               0         11 (6%)               0
                                                 ---------------------------------------------------------------
    Total.......................................       140 (16%)        3 (0.3%)        18 (10%)          2 (1%)
----------------------------------------------------------------------------------------------------------------
                                                                NDA
                                                                BLA
FY 2014                                                       N = 943
                                                              N = 194
                                                       (% of Open NDA PMRs)
                                                       (% of Open BLA PMRs)
----------------------------------------------------------------------------------------------------------------
Reporting authority/PMR status                           Delayed      Terminated         Delayed      Terminated
----------------------------------------------------------------------------------------------------------------
Accelerated approval............................        6 (0.6%)        2 (0.2%)          2 (1%)               0
PREA............................................         67 (7%)        2 (0.2%)          5 (3%)          3 (2%)
Animal efficacy.................................               0               0               0               0
FDAAA safety (since March 25, 2008).............         45 (5%)        4 (0.4%)         14 (7%)               0
                                                 ---------------------------------------------------------------
    Total.......................................       118 (13%)        8 (0.8%)        21 (11%)          3 (2%)
----------------------------------------------------------------------------------------------------------------
\1\ Percentages may not total 100 due to rounding.


[[Page 75418]]


                               Table 6--Summary of Open Postmarketing Commitments
                         [Numbers as of September 30, 2013, and September 30, 2014] \1\
----------------------------------------------------------------------------------------------------------------
                                                              FY 2013                         FY 2014
                                                 ---------------------------------------------------------------
                                                  NDA N = 264 (%  BLA N = 251 (%  NDA N = 207 (%  BLA N = 228 (%
                                                    Open PMCs)      Open PMCs)      Open PMCs)      Open PMCs)
----------------------------------------------------------------------------------------------------------------
On-Schedule:
  Pending.......................................        97 (37%)        88 (35%)        61 (29%)        69 (30%)
  Ongoing.......................................        61 (23%)        61 (24%)        49 (24%)        76 (33%)
  Submitted.....................................        45 (17%)        37 (15%)        31 (15%)        30 (13%)
                                                 ---------------------------------------------------------------
    Total.......................................       203 (77%)       186 (74%)       141 (68%)       175 (77%)
Off-Schedule:
  Delayed.......................................        56 (21%)        63 (25%)        63 (30%)        51 (22%)
  Terminated....................................          5 (2%)        2 (0.8%)          3 (1%)          2 (1%)
                                                 ---------------------------------------------------------------
    Total.......................................        61 (23%)        65 (26%)        66 (32%)        53 (23%)
----------------------------------------------------------------------------------------------------------------
\1\ Percentages may not total 100 due to rounding.


                    Table 7--Summary of Closed \1\ Postmarketing Requirements and Commitments
                         [Numbers as of September 30, 2013, and September 30, 2014] \2\
----------------------------------------------------------------------------------------------------------------
                                                              FY 2013                         FY 2014
           Postmarketing requirements            ---------------------------------------------------------------
                                                    NDA N = 134     BLA N = 17      NDA N = 188     BLA N = 30
----------------------------------------------------------------------------------------------------------------
Closed PMRs (% of Total Closed PMRs):
    Requirement met (fulfilled).................        71 (53%)        15 (88%)       136 (72%)        23 (77%)
    Requirement not met (released and new               27 (20%)          1 (6%)         14 (7%)         3 (10%)
     revised requirement issued)................
    Requirement no longer feasible or drug              36 (27%)          1 (6%)        38 (20%)         4 (13%)
     product withdrawn (released)...............
----------------------------------------------------------------------------------------------------------------
                                                              FY 2013
                                                              FY 2014
                                                 ---------------------------------------------------------------
Postmarketing commitments                                    NDA             BLA             NDA             BLA
                                                          N = 53          N = 33          N = 96          N = 70
----------------------------------------------------------------------------------------------------------------
Closed PMCs (% of Total Closed PMCs):
    Requirement met (fulfilled).................        42 (79%)        28 (85%)        84 (88%)        57 (81%)
    Requirement not met (released and new                      0               0               0          2 (3%)
     revised requirement issued)................
    Requirement no longer feasible or drug              11 (21%)         5 (15%)        12 (13%)        11 (16%)
     product withdrawn (released)...............
----------------------------------------------------------------------------------------------------------------
\1\ The table shows data for only those PMRs/PMCs that were closed (fulfilled or released) within the fiscal
  year. Therefore, data for PMRs/PMCs that were closed in prior fiscal years are not included.
\2\ Percentages may not total 100 due to rounding.


                          Table 8--Summary of Status of Postmarketing Requirements Established Between FY 2008 and FY 2014 1 2
                                                         [Numbers as of September 30, 2014] \3\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                 Fiscal year of PMR establishment
  PMR status as of FY 2014 (% of total   ---------------------------------------------------------------------------------------------------------------
    PMRs in each establishment year)           2008            2009            2010            2011            2012            2013            2014
--------------------------------------------------------------------------------------------------------------------------------------------------------
Pending.................................         11 (9%)         15 (6%)        29 (13%)        43 (17%)        60 (29%)       128 (49%)       226 (87%)
Ongoing.................................        20 (16%)        51 (20%)        49 (21%)        74 (29%)        58 (28%)        62 (24%)         23 (9%)
Submitted...............................         1 (<1%)         11 (5%)         21 (9%)          8 (3%)         15 (7%)         19 (7%)         1 (<1%)
Delayed.................................         11 (9%)        26 (11%)         18 (8%)         19 (7%)         18 (9%)         19 (7%)               0
Terminated..............................               0         2 (<1%)               0               0         1 (<1%)          3 (1%)         1 (<1%)
Released................................        28 (22%)        51 (21%)        22 (10%)        43 (17%)        20 (10%)          8 (3%)         1 (<1%)
Fulfilled...............................        57 (45%)        88 (36%)        92 (40%)        72 (28%)        33 (16%)         23 (9%)          8 (3%)
                                         ---------------------------------------------------------------------------------------------------------------
    Total...............................             128             244             231             259             205             262             260
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ The establishment date is the date of the formal FDA communication to the applicant that included the final FDA required (PMR) or requested (PMC)
  postmarketing study or clinical trial.
\2\ The table shows data for PMRs that were closed (fulfilled or released) as of FY2014. Therefore, data for PMRs that were closed in prior fiscal years
  are included.
\3\ Percentages may not total 100 due to rounding.


[[Page 75419]]


                           Table 9--Summary of Status of Postmarketing Commitments Established Between FY 2008 and FY 2014 1 2
                                                          [Numbers as of September 30, 2014] 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                 Fiscal year of PMC establishment
PMC status as of FY2014 (% of total PMCs ---------------------------------------------------------------------------------------------------------------
       in each establishment year)             2008            2009            2010            2011            2012            2013            2014
--------------------------------------------------------------------------------------------------------------------------------------------------------
Pending.................................          1 (1%)          4 (9%)          3 (3%)        11 (13%)        12 (23%)        22 (45%)        47 (82%)
Ongoing.................................         11 (9%)         5 (11%)        16 (18%)        25 (30%)        16 (30%)        14 (29%)         9 (16%)
Submitted...............................          1 (1%)         6 (13%)         9 (10%)          2 (2%)          5 (9%)         6 (12%)               0
Delayed.................................          8 (7%)         8 (17%)        16 (18%)         8 (10%)         6 (11%)          3 (6%)               0
Terminated..............................               0          1 (2%)               0               0               0               0               0
Released................................        12 (10%)          3 (6%)          6 (7%)          7 (9%)               0               0               0
Fulfilled...............................        86 (72%)        20 (43%)        40 (44%)        29 (35%)        14 (26%)          4 (8%)          1 (2%)
                                         ---------------------------------------------------------------------------------------------------------------
    Total...............................             119              47              90              82              53              49              57
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ The establishment date is the date of the formal FDA communication to the applicant that included the final FDA required (PMR) or requested (PMC)
  postmarketing study or clinical trial.
\2\ The table shows data for PMCs that were closed (fulfilled or released) as of FY2014. Therefore, data for PMCs that were closed in prior fiscal years
  are included.
\3\ Percentages may not total 100 due to rounding.


    Dated: October 25, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-26247 Filed 10-28-16; 8:45 am]
BILLING CODE 4164-01-P