[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.
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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