[Federal Register Volume 75, Number 216 (Tuesday, November 9, 2010)]
[Notices]
[Pages 68802-68806]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-28193]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2010-N-0369]
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 Food and Drug Administration Modernization Act of
1997 (Modernization Act), the Food and Drug Administration (FDA) is
required to report annually in the Federal Register on the status of
postmarketing requirements and commitments 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. 6464, Silver Spring, MD 20993-0002, 301-
796-0700; or
Robert Yetter, Center for Biologics Evaluation and Research (HFM-
25), Food and Drug Administration, 1400 Rockville Pike, Rockville, MD
20852, 301-827-0373.
SUPPLEMENTARY INFORMATION:
I. Background
A. The Modernization Act
Section 130(a) of the Modernization Act (Pub. L. 105-115) amended
the Federal Food, Drug, and Cosmetic Act (the FD&C Act) by adding a new
provision requiring reports of certain postmarketing studies, including
clinical trials, for human drug and biological products (section 506B
of the FD&C Act (21 U.S.C. 356b)). Section 506B of the FD&C Act
provides FDA with additional authority to monitor the progress of a
postmarketing study or clinical trial that an applicant has been
required to or has agreed to conduct by requiring the applicant to
submit a report annually providing information
[[Page 68803]]
on the status of the postmarketing study/clinical trial. This report
must also include reasons, if any, for failure to complete the study/
clinical trial. These studies and clinical trials are intended to
further define the safety, efficacy, or optimal use of a product and
therefore play a vital role in fully characterizing the product.
Under the Modernization Act, commitments to conduct postmarketing
studies or clinical trials included both studies/clinical trials that
applicants agreed to conduct as well as studies/clinical trials that
applicants were required to conduct under FDA regulations.\1\
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\1\ Before passage of FDAAA, FDA could require postmarketing
studies and clinical trials under the following circumstances: To
verify and describe clinical benefit for a human drug approved in
accordance with the accelerated approval provisions in section
506(b)(2)(A) of the FD&C Act (21 U.S.C. 356(b)(2)(A); 21 CFR 314.510
and 601.41); for a drug 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)); and for marketed drugs that are
not adequately labeled for children under section 505B of the FD&C
Act (Pediatric Research Equity Act (21 U.S.C. 355c; Public Law 108-
155)).
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B. The Food and Drug Administration Amendments Act of 2007
On September 27, 2007, the President signed Public Law 110-85, the
Food and Drug Administration Amendments Act of 2007 (FDAAA). Section
901, in Title IX of FDAAA, created a new section 505(o) of the FD&C Act
authorizing FDA to require certain studies and clinical trials for
human drug and biological products approved under section 505 of the
FD&C Act or section 351 of the Public Health Service Act. Under FDAAA,
FDA has been given additional authority to require applicants to
conduct and report on 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 product.
This new authority became effective on March 25, 2008. FDA may now take
enforcement action against applicants who fail to conduct studies and
clinical trials required under FDAAA, as well as studies and clinical
trials required under FDA regulations (see 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)).
Although regulations implementing the Modernization Act
postmarketing authorities use the term ``postmarketing commitment'' to
refer to both required studies and studies applicants agree to conduct,
in light of the new authorities enacted in FDAAA, FDA has decided it is
important to distinguish between enforceable postmarketing requirements
and unenforceable postmarketing commitments. Therefore, in this notice
and report, FDA refers to studies/clinical trials that an applicant is
required to conduct as ``postmarketing requirements'' (PMRs) and
studies/clinical trials that an applicant agrees to but is not required
to conduct as ``postmarketing commitments'' (PMCs). Both are addressed
in this notice and report.
C. FDA's Implementing Regulations
On October 30, 2000 (65 FR 64607), FDA published a final rule
implementing section 130 of the Modernization Act. This rule modified
the annual report requirements for new drug applications (NDAs) and
abbreviated new drug applications (ANDAs) by revising Sec.
314.81(b)(2)(vii) (21 CFR 314.81(b)(2)(vii)). The rule also created a
new annual reporting requirement for biologics license applications
(BLAs) by establishing Sec. 601.70 (21 CFR 601.70). The rule described
the content and format of the annual progress report, and clarified the
scope of the reporting requirement and the timing for submission of the
annual progress reports. The rule became effective on April 30, 2001.
The regulations apply only to human drug and biological products that
are approved under NDAs, ANDAs, and BLAs. They do not apply to animal
drugs or to biological products regulated under the medical device
authorities.
The reporting requirements under Sec. Sec. 314.81(b)(2)(vii) and
601.70 apply to PMRs and PMCs made on or before the enactment of the
Modernization Act (November 21, 1997), as well as those made after that
date. Therefore, studies and clinical trials required under FDAAA are
covered by the reporting requirements in these regulations.
Sections 314.81(b)(2)(vii) and 601.70 require applicants of
approved drug and biological products to submit annually a report on
the status of each clinical safety, clinical efficacy, clinical
pharmacology, and nonclinical toxicology study/clinical trial that is
required by FDA or that they have committed to conduct either at the
time of approval or after approval of their NDA, ANDA, or BLA. The
status of PMCs concerning chemistry, manufacturing, and production
controls and the status of other studies/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. It should be noted, however, that applicants are required to
report to FDA on these commitments made for NDAs and ANDAs under Sec.
314.81(b)(2)(viii). Furthermore, section 505(o)(3)(E) of the FD&C Act
as amended by FDAAA requires that applicants report periodically on the
status of each required study/clinical trial and each study/clinical
trial ``otherwise undertaken * * * to investigate a safety issue * *
*.''
According to the regulations, once a PMR has been required or a PMC
has been agreed upon, an applicant must report on the progress of the
PMR/PMC on the anniversary of the product's approval 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 progress report 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/clinical trial, and (3) submission of the final report to FDA.
The status of the PMR/PMC must be described in the annual report
according to the following definitions:
Pending: The study/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);
Ongoing: The study/clinical trial is proceeding according
to or ahead of the original schedule;
Delayed: The study/clinical trial is behind the original
schedule;
Terminated: The study/clinical trial was ended before
completion, but a final report has not been submitted to FDA; or
Submitted: The study/clinical trial has been completed or
terminated, and a final report has been submitted to FDA.
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).
II. Summary of Information From Postmarketing Status Reports
This report, published to fulfill the annual reporting requirement
under the Modernization Act, summarizes the
[[Page 68804]]
status of PMRs and PMCs as of September 30, 2009. If a requirement or
commitment did not have a schedule, or a postmarketing progress report
was not received in the previous 12 months, the PMR/PMC is categorized
according to the most recent information available to the Agency.\2\
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\2\ Although the data included in this report do not include a
summary of reports that sponsors have failed to file by their due
date, the Agency notes that it may take appropriate regulatory
action in the event reports are not filed on a timely basis.
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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, including PMRs required under FDAAA
(section 505(o)(3) of the FD&C Act), PMRs required under FDA
regulations (e.g., PMRs required to demonstrate clinical benefit of a
product following accelerated approval (see footnote 1 of this
document)), and PMCs agreed to by the applicant.
Information summarized in this report includes the following: (1)
The number of applicants with open (uncompleted) PMRs/PMCs, (2) the
number of open PMRs/PMCs, (3) the status of open PMRs/PMCs as reported
in Sec. 314.81(b)(2)(vii) or Sec. 601.70 annual reports, (4) the
status of concluded PMRs/PMCs as determined by FDA, and (5) the number
of applications with open PMRs/PMCs for which applicants did not submit
an annual report within 60 days of the anniversary date of U.S.
approval.
Additional information about PMRs/PMCs submitted by applicants to
CDER and CBER is provided on FDA's Web site at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm. Neither the Web site nor this
notice 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 reviewed for accuracy. Numbers
published in this notice cannot be compared with the numbers resulting
from searches of the Web site because this notice incorporates totals
for all PMRs/PMCs in FDA databases, including PMRs/PMCs undergoing
review for accuracy. In addition, the report in this notice will be
updated annually while the Web site is updated quarterly (i.e., in
January, April, July, and October).
Many applicants have more than one approved product and for many
products there is more than one PMR or PMC. Specifically, there were
163 unique applicants with 242 NDAs/ANDAs that had open PMRs/PMCs.
There were 59 unique applicants with 91 BLAs that had open PMRs/PMCs.
Annual status reports are required to be submitted for each open
PMR/PMC within 60 days of the anniversary date of U.S. approval of the
original application. In fiscal year 2009 (FY09), 25 percent (48/193)
of NDA/ANDA and 34 percent (31/91) of BLA annual status reports were
not submitted within 60 days of the anniversary date of U.S. approval
of the original application. Of the annual status reports due but not
submitted on time, 100 percent of the NDA/ANDA and 45 percent (14/31)
of the BLA reports were submitted before the close of FY09 (September
30, 2009).
Most PMRs are progressing on schedule (91.5 percent for NDAs/ANDAs;
92 percent for BLAs). Most PMCs are also progressing on schedule (89
percent for NDAs/ANDAs; 75 percent for BLAs). Most of the PMCs that are
currently listed in the database were developed before the
postmarketing requirements section of FDAAA took effect.\3\
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\3\ There are existing PMCs established before FDAAA that might
meet current FDAAA standards for required safety studies/clinical
trials under section 505(o)(3)(B) of the FD&C Act (21 U.S.C.
355(o)(3)(B)). Under section 505(o)(3)(c), the Agency may convert
pre-existing PMCs into PMRs if it becomes aware of new safety
information.
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III. About This Report
This report provides six separate summary tables. The tables
distinguish between PMRs and PMCs and between on-schedule and off-
schedule PMRs and PMCs according to the original schedule milestones.
On-schedule PMRs/PMCs are categorized as pending, ongoing, or
submitted. Off-schedule PMRs/PMCs that have missed one of the original
milestone dates are categorized as delayed or terminated. The tables
include data as of September 30, 2009.
Table 1 of this document provides an overall summary of the data on
all PMRs and PMCs. Tables 2 and 3 of this document provide detail on
PMRs. Table 2 provides additional detail on the status of on-schedule
PMRs.
Table 1 shows that most PMRs (91.5 percent for NDAs/ANDAs and 92
percent for BLAs) and most PMCs (89 percent for NDAs/ANDAs and 75
percent for BLAs) are on schedule. Overall, of the PMRs that are
pending (i.e., have not been initiated), 83 percent were created within
the past 3 years. Table 2 shows that 62 percent of pending PMRs for
drug and biological products are in response to the Pediatric Research
and Equity Act (PREA), under which FDA requires sponsors to study new
drugs, when appropriate, for pediatric populations. Under section
505B(a)(3) of the FD&C Act, the initiation of these studies generally
is deferred until required safety information from other studies has
first been submitted and reviewed. PMRs for 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 product is used for
its indication as a counterterrorism measure. In the absence of a
public health emergency, these studies/clinical trials will remain
pending indefinitely. The next largest category of pending PMRs for
drug and biological products (35 percent) comprises those studies/
clinical trials required by FDA under FDAAA, which became effective on
March 25, 2008.
Table 3 provides additional detail on the status of off-schedule
PMRs. The majority of off-schedule PMRs (which account for 8.5 percent
of the total for NDAs/ANDAs and 9 percent for BLAs) are delayed
according to the original schedule milestones (94 percent (31/33) for
NDAs/ANDAs; 88 percent (\7/8\) for BLAs). In certain situations, the
original schedules may have been adjusted for unanticipated delays in
the progress of the study/clinical trial (e.g., difficulties with
subject enrollment in a trial for a marketed drug or need for
additional time to analyze results). In this report, study/clinical
trial status reflects the status in relation to the original study/
clinical trial schedule regardless of whether FDA has acknowledged that
additional time may be required to complete the study/clinical trial.
Tables 4 and 5 of this document provide additional detail on the
status of PMCs. Table 4 provides additional detail on the status of on-
schedule PMCs. Pending PMCs comprise 52 percent (449/867) of the on-
schedule NDA and ANDA PMCs and 34 percent (82/244) of the on-schedule
BLA PMCs.
Table 5 provides additional details on the status of off-schedule
PMCs. The majority of off-schedule PMCs (which account for 11 percent
for NDAs/ANDAs and 25 percent for BLAs) are delayed according to the
original schedule milestones (90 percent (100/111) for NDAs/ANDAs; 98
percent (79/81) for BLAs). As noted above, this report reflects the
original due dates for study/clinical trial results and does not
reflect discussions between the Agency and the sponsor regarding
studies/clinical trials that may require more time for completion.
Table 6 of this document provides details about PMRs and PMCs that
were concluded in the previous year. Most concluded PMRs and PMCs were
fulfilled (60 percent of NDA/ANDA PMRs and 56 percent of BLA PMRs; 79
[[Page 68805]]
percent of NDA/ANDA PMCs and 82 percent of BLA PMCs). Compared to FY08,
in FY09 there has been a significant increase in the number of
concluded PMRs and the number of concluded PMCs for drug and biological
products.
Table 1--Summary of Postmarketing Requirements and Commitments
[Numbers as of September 30, 2009]
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NDA/ANDA (% of >BLA (% of total
total PMR or % of PMR or % of total
total PMC) PMC)\1\
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Number of open PMRs........... 405 96
On-schedule open PMRs (see 372 (91.5%) 88 (92%)
table 2 of this document)
Off-schedule open PMRs 33 (8.5%) 8 (9%)
(see table 3 of this
document)................
Number of open PMCs........... 978 325
On-schedule open PMCs (see 867 (89%) 244 (75%)
table 4 of this document)
Off-schedule open PMCs 111 (11%) 81 (25%)
(see table 5 of this
document)................
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\1\ On October 1, 2003, FDA completed a consolidation of certain
therapeutic products formerly regulated by CBER into CDER.
Consequently, CDER now reviews many BLAs. Fiscal year statistics for
postmarketing requirements and commitments for BLAs reviewed by CDER
are included in BLA totals in this table.
Table 2--Summary of On-Schedule Postmarketing Requirements
[Numbers as of September 30, 2009]
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NDA/ANDA (% of BLA (% of total
On-schedule open PMRs total PMR PMR) \1\
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Pending (by type):
Accelerated approval...... 6 4
PREA \2\.................. 185 26
Animal efficacy \3\....... 2 0
FDAAA safety (since March 85 35
25, 2008)................
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Total................. 278 (68.5%) 65 (68%)
Ongoing:
Accelerated approval...... 16 5
PREA \2\.................. 23 5
Animal efficacy \3\....... 0 0
FDAAA safety (since March 19 9
25, 2008)................
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Total................. 58 (14%) 19 (20%)
Submitted:
Accelerated approval...... 8 0
PREA \2\.................. 23 4
Animal efficacy \3\....... 0 0
FDAAA safety (since March 5 0
25, 2008)................
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Total................. 36 (9%) 4 (4%)
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Combined total...... 372 (91.5%) 88 (92%)
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\1\ See note 1 for table 1 of this document.
\2\ Many PREA studies have a pending status. PREA studies are usually
deferred because the product is ready for approval in adults.
Initiation of these studies also may be deferred until additional
safety information from other studies has first been submitted and
reviewed.
\3\ PMRs for 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 product is used for its indication as a
counterterrorism measure. In the absence of a public health emergency,
these studies/clinical trials will remain pending indefinitely.
Table 3--Summary of Off-Schedule Postmarketing Requirements
[Numbers as of September 30, 2009]
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NDA/ANDA (% of BLA (% of total
Off-schedule open PMRs total PMR) PMR) \1\
------------------------------------------------------------------------
Delayed
Accelerated approval...... 3 2
PREA...................... 28 5
Animal efficacy........... 0 0
FDAAA safety (since March 0 0
25, 2008)................
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Total................. 31 (8%) 7 (12%)
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Terminated.................... 2 (0.5%) 1 (1%)
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[[Page 68806]]
Combined total............ 33 8
(8.5%) (9%)
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\1\ See note 1 for table 1 of this document.
Table 4--Summary of On-Schedule Postmarketing Commitments
[Numbers as of September 30, 2009]
------------------------------------------------------------------------
NDA/ANDA (% of BLA (% of total
On-Schedule Open PMCs total PMC) PMC) \1\
------------------------------------------------------------------------
Pending....................... 449 (46%) 82 (25%)
Ongoing....................... 147 (15%) 84 (26%)
Submitted..................... 271 (28%) 78 (24%)
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Combined total............ 867 (89%) 244 (75%)
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\1\ See note 1 for table 1 of this document.
Table 5--Summary of Off-Schedule Postmarketing Commitments
[Numbers as of September 30, 2009]
------------------------------------------------------------------------
NDA/ANDA (% of BLA (% of total
Off-Schedule Open PMCs total PMC) PMC) \1\
------------------------------------------------------------------------
Delayed....................... 100 (10%) 79 (24%)
Terminated.................... 11 (1%) 2 (1%)
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Combined total............ 111 (11%) 81 (25%)
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\1\ See note 1 for table 1 of this document.
Table 6--Summary of Concluded Postmarketing Requirements and Commitments
[October 1, 2008 to October 1, 2009]
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NDA/ANDA (% of BLA (% of total)
total) \1\
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Concluded PMRs:
Requirement met 28 (60%) 5 (56%)
(fulfilled)..............
Requirement not met 7 (15%) 2 (22%)
(released and new revised
requirement issued)......
Requirement no longer 12 (25%) 2 (22%)
feasible or product
withdrawn (released).....
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Total................. 47 9
Concluded PMCs:
Commitment met (fulfilled) 259 (79%) 32 (82%)
Commitment not met 21 (6%) 0
(released and new revised
requirement/commitment
issued)..................
Commitment no longer 48 (15%) 7 (18%)
feasible or product
withdrawn (released).....
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Total................. 328 39
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\1\ See note 1 for table 1 of this document.
Dated: November 3, 2010.
David Dorsey,
Acting Deputy Commissioner for Policy, Planning and Budget.
[FR Doc. 2010-28193 Filed 11-8-10; 8:45 am]
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