[Federal Register Volume 82, Number 235 (Friday, December 8, 2017)]
[Notices]
[Pages 57996-58003]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-26470]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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.
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. 7301, 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.
---------------------------------------------------------------------------
\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)).
---------------------------------------------------------------------------
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 related to the use of a
drug product (section 505(o)(3) of the FD&C Act (21 U.S.C. 355(o)(3)),
as added by the Food and Drug Administration Amendments Act of 2007
(FDAAA) (Pub. L. 110-85)).
Under the Pediatric Research Equity Act (PREA) (Pub. L.
108-155), 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 (21 U.S.C. 355c), 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
[[Page 57997]]
U.S.C. 356(c)(2)(A)) (21 CFR 314.510 and 21 CFR 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 21 CFR 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.
---------------------------------------------------------------------------
\2\ 21 CFR 314.600 for drugs; 21 CFR 601.90 for biological
products.
---------------------------------------------------------------------------
B. Reporting Requirements
Under the regulations (21 CFR 314.81(b)(2)(vii) and 21 CFR 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 Sec.
314.81(b)(2)(viii). 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 Sec. Sec. 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.
---------------------------------------------------------------------------
\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 United States 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.
---------------------------------------------------------------------------
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 Sec. Sec. 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\
---------------------------------------------------------------------------
\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''
available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM080569.pdf.
\5\ The definitions for the terms ``pending,'' ``ongoing,''
``delayed,'' ``terminated,'' and ``submitted'' are adapted from
Sec. Sec. 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.''
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\7\ In some instances, an applicant may have justifiable reasons
for delay of its PMR/PMC (see section I.D).
---------------------------------------------------------------------------
Terminated: The study or clinical trial was ended before
completion, but 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 open or closed. 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.
---------------------------------------------------------------------------
\8\ Previous FDA reports on the status of PMRs/PMCs used the
term ``completed'' to refer to PMRs/PMCs that are closed.
---------------------------------------------------------------------------
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 the deferred 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,
[[Page 57998]]
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).
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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.
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 (21
U.S.C. 356b)). 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, 2016) is not included
on the public Web site. The FDA Web site is updated quarterly.\11\ 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 it has been verified and reviewed for
suitability for public disclosure.
---------------------------------------------------------------------------
\11\ https://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm.
---------------------------------------------------------------------------
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 fiscal year (FY) 2016 (i.e., as of September 30, 2016).
Specifically, the report summarizes the status of all open PMRs/PMCs
through 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.\12\
---------------------------------------------------------------------------
\12\ Although the data included in this report do not include a
summary of reports that applicants have failed to file by their due
dates, the Agency notes that it may take appropriate regulatory
action in the event reports are not filed on a timely basis.
---------------------------------------------------------------------------
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; \13\ (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 Sec. 314.81(b)(2)(vii)
or Sec. 601.70 ASRs; (5) the status of closed PMRs/PMCs; and (6) the
distribution of the status by fiscal year of establishment \14\ (FY2010
to FY2016) for PMRs and PMCs open at the end of FY2016, or those closed
within FY2016. The tables in this report distinguish between PMRs and
PMCs, PMRs/PMCs for NDAs and BLAs, and on-schedule and off-schedule
PMRs/PMCs, according to the original schedule milestones. Additional
information about PMRs/PMCs is provided on FDA's Web site at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm.
---------------------------------------------------------------------------
\13\ At the end of FY2016, there were no PMRs/PMCs for ANDAs
that met the reporting requirements under the Food and Drug
Administration Modernization Act of 1997. Therefore, this report
reflects information for NDAs and BLAs only.
\14\ 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.
---------------------------------------------------------------------------
Numbers published in this report 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,
2016 (i.e., for FY2016). 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
[[Page 57999]]
comparison of on- or off-schedule PMRs (e.g., to assess for a potential
trend) is not appropriate. 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, 2016, there were 285 unique applicants with
open PMRs/PMCs under 890 unique NDAs and BLAs. There were 207 unique
NDA applicants (and 734 associated applications) and 78 unique BLA
applicants (and 156 associated applications) with open PMRs/PMCs.
Table 1--Applicants and Applications (NDA/BLA) With Open Postmarketing Requirements and Commitments
[Numbers as of September 30, 2016]
----------------------------------------------------------------------------------------------------------------
Total (NDA and
NDA \1\ BLA \2\ BLA)
----------------------------------------------------------------------------------------------------------------
Number of unique applicants with open PMRs/PMCs............... 207 78 285
Number of applications with open PMRs/PMCs.................... 734 156 890
----------------------------------------------------------------------------------------------------------------
\1\ As of September 30, 2016, there were only NDAs with associated PMRs/PMCs managed by CDER.
\2\ Includes BLAs managed by both CDER and CBER.
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
United States approval of the original application or an alternate
reporting date that was granted by FDA (Sec. Sec. 314.81 and
601.70).\15\ Table 2 shows that there were 764 NDAs and BLAs with an
ASR due in FY2016 (622 NDAs and 142 BLAs).\16\ Of the 622 NDA ASRs due
in that fiscal year, 66 percent (411/622) were received on time, 11
percent (66/622) were not received on time, and 23 percent (145/622)
were not received during FY2016. Of the 142 BLA ASRs due, 72 percent
(102/142) were received on time, 17 percent (24/142) were not received
on time, and 11 percent (16/142) were not received during FY2016.
---------------------------------------------------------------------------
\15\ Some applicants have requested and been granted by FDA
alternate annual reporting dates to facilitate harmonized reporting
across multiple applications.
\16\ 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 FY2016. 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.
Table 2--Annual Status Reports Received
[Numbers as of September 30, 2016] \1\
----------------------------------------------------------------------------------------------------------------
Received, on time Received, not on Expected but not
\2\ Expected \3\ (% of time \4\ (% of received (% of
expected) expected) expected)
----------------------------------------------------------------------------------------------------------------
NDA.................................... \5\ 622 411 (66%) 66 (11%) 145 (23%)
BLA.................................... 142 102 (72%) 24 (17%) 16 (11%)
------------------------------------------------------------------------
Total.............................. 764 513 (67%) 90 (12%) 161 (21%)
----------------------------------------------------------------------------------------------------------------
\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.
\5\ The total number of NDA ASRs expected in FY2016 (622) increased compared to the number of ASRs expected in
FY2015 (451). The increase is primarily due to the establishment of several FDAAA safety PMRs for which a
serious safety issue applied to a class of drug products. In those cases, each applicant with a drug product
(i.e., application) in the class was required to conduct the same postmarketing safety study or trial, and
each applicant was required to submit an ASR for that PMR. As a consequence, multiple ASRs were expected
during FY2016 for the same FDAAA safety PMR.
C. Overview of On- and Off-Schedule Open PMRs/PMCs
Table 3 shows that as of September 30, 2016, most open PMRs (84
percent for NDAs and 91 percent for BLAs) and most open PMCs (71
percent for NDAs and 83 percent for BLAs) were progressing on schedule.
Table 3--Summary of On- and Off-Schedule Postmarketing Requirements and Commitments
[Numbers as of September 30, 2016] \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Open PMRs N = 1,323 Open PMCs N = 365
---------------------------------------------------------------------------------------------------
NDA (% of open NDA BLA (% of open BLA NDA (% of open NDA BLA (% of open BLA
PMRs) PMRs) PMCs) PMCs)
--------------------------------------------------------------------------------------------------------------------------------------------------------
On-schedule......................................... 882 (84%) 247 (91%) 123 (71%) 159 (83%)
Off-schedule........................................ 169 (16%) 25 (9%) 51 (29%) 32 (17%)
---------------------------------------------------------------------------------------------------
[[Page 58000]]
Total........................................... 1,051 272 174 191
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Percentages may not total 100 due to rounding.
D. Open and On-Schedule PMRs
Table 4 shows that as of September 30, 2016, nearly half of the
open NDA and BLA PMRs were pending (49 percent (517/1,051) and 45
percent (123/272), respectively). PREA PMRs and FDAAA PMRs comprised 55
percent (349/640) and 39 percent (249/640) of pending PMRs,
respectively. The next largest category of open and on-schedule PMRs
comprised those that were ongoing (29 percent (306/1,051) of NDA PMRs
and 37 percent (100/272) of BLA PMRs).
Table 4--Summary of Open and On-Schedule Postmarketing Requirements
[Numbers as of September 30, 2016] \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
NDA N = 1,051 (% of open NDA PMRs) BLA N = 272 (% of open BLA PMRs)
Reporting authority/PMR status -----------------------------------------------------------------------------------------------
Pending Ongoing Submitted Pending Ongoing Submitted
--------------------------------------------------------------------------------------------------------------------------------------------------------
Accelerated approval.................................... 16 (2%) 19 (2%) 3 (<1%) 13 (5%) 10 (4%) 4 (1%)
PREA \2\................................................ 300 (28%) 124 (12%) 14 (1%) 49 (18%) 29 (11%) 8 (3%)
Animal efficacy \3\..................................... 4 (<1%) 0 1 (<1%) 9 (3%) 0 0
FDAAA safety............................................ 197 (19%) 163 (16%) 41 (4%) 52 (19%) 61 (22%) 12 (4%)
-----------------------------------------------------------------------------------------------
Total............................................... 517 (49%) 306 (29%) 59 (6%) 123 (45%) 100 (37%) 24 (9%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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.
E. Open and Off-Schedule PMRs
Table 5 provides additional information on the status of open and
off-schedule PMRs (i.e., delayed and terminated). At the end of
September 30, 2016, 16 percent (169/1,051) of the open NDA PMRs and 9
percent (25/272) of the open BLA PMRs were off schedule. Of the off-
schedule NDA PMRs, 97 percent (164/169) were off schedule because they
were delayed and the remaining 3 percent (5/169) were terminated.
Similarly, 88 percent of the off-schedule BLA PMRs were delayed (22/
25).
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 the need for additional time to analyze results). In
this report, study or clinical trial status reflects the status in
relation to the original \17\ study or clinical trial schedule
regardless of whether FDA has acknowledged that additional time was
required to complete the study or clinical trial.
---------------------------------------------------------------------------
\17\ With the exception of PREA PMRs for which a deferral
extension of the final report submission date has been granted.
Table 5--Summary of Open and Off-Schedule Postmarketing Requirements
[Numbers as of September 30, 2016] \1\
----------------------------------------------------------------------------------------------------------------
NDA N = 1,051 (% of open NDA BLA N = 272 (% of open BLA
PMRs) PMRs)
Reporting authority/PMR status ---------------------------------------------------------------
Delayed Terminated Delayed Terminated
----------------------------------------------------------------------------------------------------------------
Accelerated approval............................ 9 (1%) 1 (<1%) 1 (<1%) 0
PREA............................................ 84 (8%) 2 (<1%) 6 (2%) 2 (1%)
Animal efficacy................................. 0 0 0 0
FDAAA safety.................................... 71 (7%) 2 (<1%) 15 (6%) 1 (<1%)
---------------------------------------------------------------
[[Page 58001]]
Total....................................... 164 (16%) 5 (<1%) 22 (8%) 3 (1%)
----------------------------------------------------------------------------------------------------------------
\1\ Percentages may not total 100 due to rounding.
F. Open On-Schedule and Off-Schedule PMCs
Table 6 provides the status of open on-schedule and off-schedule
PMCs. As of September 30, 2016, most open, on-schedule NDA PMCs were
pending (36 percent; 62/174) and most open, on-schedule BLA PMCs were
ongoing (43 percent; 83/191). Fewer open NDA and BLA PMCs were
considered off schedule (29 percent (51/174) and 17 percent (32/191),
respectively). The majority of off-schedule NDA and BLA PMCs were
delayed according to the original schedule milestones.
Table 6--Summary of Open Postmarketing Commitments
[Numbers as of September 30, 2016] \1\
------------------------------------------------------------------------
NDA N = 174 (% BLA N = 191 (%
open PMCs) open PMCs)
------------------------------------------------------------------------
On-Schedule:
Pending..................... 62 (36%) 52 (27%)
Ongoing..................... 40 (23%) 83 (43%)
Submitted................... 21 (12%) 24 (13%)
---------------------------------------
Total................... 123 (71%) 159 (83%)
------------------------------------------------------------------------
Off-Schedule:
Delayed..................... 50 (29%) 30 (16%)
Terminated.................. 1 (1%) 2 (1%)
---------------------------------------
Total................... 51 (29%) 32 (17%)
------------------------------------------------------------------------
\1\ Percentages may not total 100 due to rounding.
G. Closed PMRs and PMCs
Table 7 provides details about PMRs and PMCs that were closed
(fulfilled or released) within FY2016. The majority of closed PMRs were
fulfilled (72 percent of NDA PMRs and 82 percent of BLA PMRs) at the
end of FY2016. Similarly, the majority of closed PMCs were fulfilled at
the end of FY2016.
Table 7--Summary of Closed \1\ Postmarketing Requirements and
Commitments
[Numbers as of September 30, 2016] \2\
------------------------------------------------------------------------
NDA BLA
------------------------------------------------------------------------
Postmarketing Requirements
Closed PMRs (% of Total Closed PMRs).... N = 174 N = 33
Requirement met (fulfilled)......... 126 (72%) 27 (82%)
Requirement not met (released and 19 (11%) 4 (12%)
new revised requirement issued)....
Requirement no longer feasible or 29 (17%) 2 (6%)
drug product withdrawn (released)..
Postmarketing Commitments
Closed PMCs (% of Total Closed PMCs).... N= 54 N=28
Requirement met (fulfilled)......... 44 (82%) 23 (82%)
Requirement not met (released and 1 (2%) 1 (4%)
new revised requirement issued)....
Requirement no longer feasible or 9 (17%) 4 (14%)
drug product withdrawn (released)..
------------------------------------------------------------------------
\1\ The table shows data for those PMRs/PMCs that were closed (fulfilled
or released) within FY2016. Therefore, data for PMRs/PMCs that were
closed in prior fiscal years are not included.
\2\ Percentages may not total 100 due to rounding.
[[Page 58002]]
H. Distribution of the Statuses of PMRs and PMCs
Tables 8 and 9 show the distribution of the statuses of PMRs/PMCs
as of September 30, 2016, presented by the years that the PMRs/PMCs
were established \18\ (FY2010 to FY2016).\19\ \20\ Note that the data
shown for closed (fulfilled or released) PMRs/PMCs are for all PMRs/
PMCs that were closed as of FY2016. Therefore, data for PMRs/PMCs that
were closed in prior fiscal years are included.
---------------------------------------------------------------------------
\18\ 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.
\19\ Tables 8 and 9 include data for only the past 7 fiscal
years. Data on the distribution of statuses for PMRs/PMCs
established in FY2009 and as of FY2015 are presented in the FY2015
status of postmarketing requirements and commitments report (81 FR
85573) (https://www.federalregister.gov/d/2016-28442).
\20\ The total number of PMRs/PMCs established in FY2010 through
FY2016 reflects the data in FDA's databases as of September 30,
2016. Because of data corrections and improvements in ascertaining
the PMR/PMC establishment date, some of the total numbers of PMRs/
PMCs established in each fiscal year are different from those
reported in the prior fiscal year's (FY2015) Federal Register
report.
---------------------------------------------------------------------------
Based on the data shown in table 8, an average of 261 PMRs were
established each year since FY2010.\21\ Most PMRs that were established
in the earlier years were either fulfilled or released. For example, as
of September 30, 2016, 54 percent (122/224) of the PMRs that were
established in FY2010 were fulfilled, and 12 percent (27/224) 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,
2016, 86 percent (232/269) of the PMRs established in FY2016 were
pending, and 8 percent (22/269) were ongoing. Overall, of the PMRs that
were pending as of September 30, 2016, 83 percent (510/614) were
created within the past 3 years (FY2014, FY2015, and FY2016). Finally,
table 8 shows that, on average, 7 percent (137/1,829) of the PMRs
established since FY2010 were delayed as of September 30, 2016.
---------------------------------------------------------------------------
\21\ 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) had 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.
Table 8--Summary of Status of Postmarketing Requirements Established \1\ Between FY2010 and FY2016 \2\
[Numbers as of September 30, 2016] \3\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Fiscal year of PMR establishment
PMR status as of FY2016 (% of total PMRs in each ------------------------------------------------------------------------------------------
establishment year) 2010 2011 2012 2013 2014 2015 2016
--------------------------------------------------------------------------------------------------------------------------------------------------------
Pending...................................................... 8 (4%) 16 (6%) 24 (11%) 56 (20%) 114 (39%) 164 (58%) 232 (86%)
Ongoing...................................................... 26 (12%) 49 (19%) 52 (24%) 69 (25%) 80 (27%) 52 (18%) 22 (8%)
Submitted.................................................... 15 (7%) 7 (3%) 9 (4%) 8 (3%) 12 (4%) 16 (6%) 2 (1%)
Delayed...................................................... 26 (12%) 18 (7%) 25 (11%) 30 (11%) 25 (9%) 13 (4%) 0
Terminated................................................... 0 2 (<1%) 1 (<1%) 0 0 1 (<1%) 0
Released..................................................... 27 (12%) 59 (23%) 30 (14%) 33 (12%) 14 (5%) 5 (2%) 4 (2%)
Fulfilled.................................................... 122 (54%) 110 (42%) 79 (36%) 82 (29%) 48 (16%) 33 (12%) 9 (3%)
------------------------------------------------------------------------------------------
Total \4\................................................ 224 261 220 278 293 284 269
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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 FY2016. Therefore, data for PMRs that were closed in prior fiscal years
are included.
\3\ Percentages may not total 100 due to rounding.
\4\ The total number of PMRs/PMCs established in FY2010 through FY2016 reflects the data in FDA's databases as of September 30, 2016. Because of data
corrections and improvements in ascertaining the PMR/PMC establishment date, some of the total numbers of PMRs/PMCs established in each fiscal year
are different from those reported in the prior fiscal year's (FY2015) Federal Register report.
Table 9 provides an overview of PMCs in a similar format as table 8
for PMRs. The results for PMCs are similar to those for PMRs as
described above and in table 8.
Table 9--Summary of Status of Postmarketing Commitments Established \1\ Between FY2010 and FY2016 \2\
[Numbers as of September 30, 2016] \3\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Fiscal year of PMC establishment
PMR status as of FY2016 (% of total PMCs in each ------------------------------------------------------------------------------------------
establishment year) 2010 2011 2012 2013 2014 2015 2016
--------------------------------------------------------------------------------------------------------------------------------------------------------
Pending...................................................... 1 (1%) 3 (4%) 0 3 (7%) 8 (14%) 25 (40%) 48 (80%)
Ongoing...................................................... 11 (12%) 17 (21%) 11 (27%) 16 (35%) 19 (34%) 18 (28%) 4 (7%)
Submitted.................................................... 8 (9%) 1 (1%) 2 (5%) 3 (7%) 7 (13%) 1 (2%) 2 (3%)
Delayed...................................................... 13 (14%) 5 (6%) 4 (10%) 3 (7%) 0 5 (8%) 0
Terminated................................................... 0 0 0 0 0 0 0
Released..................................................... 10 (11%) 12 (15%) 1 (2%) 1 (2%) 0 1 (2%) 0
Fulfilled.................................................... 51 (54%) 42 (53%) 23 (56%) 20 (43%) 22 (39%) 13 (21%) 6 (10%)
------------------------------------------------------------------------------------------
Total \4\................................................ 94 80 41 46 56 63 60
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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.
[[Page 58003]]
\2\ The table shows data for PMCs that were closed (fulfilled or released) as of FY2016. Therefore, data for PMCs that were closed in prior fiscal years
are included.
\3\ Percentages may not total 100 due to rounding.
\4\ The total number of PMRs/PMCs established in FY2010 through FY2016 reflects the data in FDA's databases as of September 30, 2016. Because of data
corrections, as well as improvements in ascertaining the PMR/PMC establishment date, some of the total numbers of PMRs/PMCs established in each fiscal
year are different from those reported in the prior fiscal year's (FY2015) Federal Register report.
Dated: December 4, 2017.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017-26470 Filed 12-7-17; 8:45 am]
BILLING CODE 4164-01-P