[Federal Register Volume 74, Number 171 (Friday, September 4, 2009)]
[Notices]
[Pages 45867-45872]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-21302]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2009-N-0233]
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 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 (Public Law 105-115)
amended the Federal Food, Drug, and Cosmetic Act (the 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 act (21 U.S.C. 356(b)). Section 506B of the 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
[[Page 45868]]
providing information 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\ 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 (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 (Pediatric Research Equity Act (21
U.S.C. 355B; 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 act
authorizing FDA to require certain studies and clinical trials for
human drug and biological products approved under section 505 of the
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) of the act; 21 U.S.C. 355(o)(1), 352(z), and 333(f)).
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)(1)(E) of the 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 subject
accrual or initiation of an animal study, (3) completion of the study/
clinical trial, and (4) 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 status of PMRs and PMCs as
of September 30, 2008. If a requirement or commitment did not have a
schedule, or
[[Page 45869]]
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.
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 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.,
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
158 unique applicants with 297 NDAs/ANDAs that had open PMRs/PMCs.
There were 54 unique applicants with 94 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 (FY) 2008, 27 percent (59/215) of
NDA/ANDA and 52 percent (43/83) of BLA annual status reports were
reported late or were overdue at the close of the FY, September 30,
2008. Of the annual status reports due but not submitted within 60 days
of the anniversary date of U.S. approval of the original application,
100 percent (59/59) of the NDA/ANDA and 42 percent (18/43) of the BLA
reports were submitted before September 30, 2008.
Most PMRs are progressing on schedule (95 percent for NDAs/ANDAs;
89 percent for BLAs). Most PMCs are also progressing on schedule (96
percent for NDAs/ANDAs; 78 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.\2\
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\2\ Although there are PMCs that might meet FDAAA standards for
required safety studies/clinical trials under section 505(o)(3)(B)
of the act (21 U.S.C. 355(o)(3)(B)) if they were first determined to
be necessary today, they may be converted to PMRs only if FDA
becomes aware of new safety information.
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III. What's New About This Report
This report now provides six separate tables instead of one summary
table. 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, 2008.
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 of this document provides additional detail on the status
of on-schedule PMRs.
Table 1 of this document shows that most PMRs (95 percent for NDAs/
ANDAs and 89 percent for BLAs) and most PMCs (96 percent for NDAs/ANDAs
and 78 percent for BLAs) are on schedule. Overall, of the PMRs that are
pending (i.e., have not been initiated), 73 percent were created within
the past 3 years.
Table 2 of this document shows that most pending PMRs for both 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 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
comprises those studies/clinical trials required by FDA under FDAAA,
which became effective on March 25, 2008.
Section 921 of FDAAA requires FDA to review the backlog of
postmarketing safety commitments and report to Congress. CDER
contracted with an external group to review the backlog of its PMRs/
PMCs as well as PMR/PMC annual status reports.\3\ The contractors's
report was recently completed and can be found on the FDA Web site at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/ucm064436.htm. As Exhibit 9 of the report
shows, the external review has resulted in a decreased number of NDA
PMRs/PMCs categorized as pending because their statuses have been
updated to other categories (e.g., submitted). Some of this decrease is
reflected in the NDA statistics reported in this notice, which shows
the status of the PMRs/PMCs as of September 30, 2008, and additional
status changes will be reflected in the statistics reported in the next
annual notice showing the status of the PMRs/PMCs as of September 30,
2009.
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\3\ The external backlog review covered PMRs/PMCs for NDAs and
CDER-regulated BLAs. CBER conducted a separate backlog review of the
CBER-regulated BLAs.
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[[Page 45870]]
Table 3 of this document provides additional detail on the status
of off-schedule PMRs. The majority of off-schedule PMRs (which account
for only 5 percent of the total for NDAs/ANDAs and 11 percent for BLAs)
are delayed according to the original schedule milestones (93 percent
(13/14) for NDAs/ANDAs; 71 percent (5/7) for BLAs). However, after
discussion between FDA and applicants, 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 status reflects the status in relation to the
original study schedule regardless of whether adjustments to the
schedule have been made.
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 56 percent (544/965) of the on-
schedule NDA and ANDA PMCs and 40 percent (112/279) of the on-schedule
BLA PMCs.
Table 5 of this document provides additional details on the status
of off-schedule PMCs. The majority of off-schedule PMCs (which account
for only 4 percent for NDAs/ANDAs and 22 percent for BLAs) are delayed
according to the original schedule milestones (91 percent (39/43) for
NDAs/ANDAs; 97 percent (76/78) for BLAs). However, after discussion
between FDA and applicants, 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).
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 (80 percent of NDA/ANDA PMRs and 70 percent of BLA PMRs; 86
percent of NDA/ANDA PMCs and 97 percent of BLA PMCs).
Table 1.--Summary of Postmarketing Requirements and Commitments (Numbers
as of September 30, 2008)
------------------------------------------------------------------------
NDA/ANDA (% of Total PMR or BLA (% of Total PMR or % of
% of Total PMC) Total PMC)\1\
------------------------------------------------------------------------
Number of 306 65
open PMRs
------------------------------------------------------------------------
On- 292 (95%) 58 (89%)
schedule
open PMRs
(see
table 2
of this
document)
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Off- 14 (5%) 7 (11%)
schedule
open PMRs
(see
table 3
of this
document)
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Number of 1,008 357
open PMCs
------------------------------------------------------------------------
On- 965 (96%) 279 (78%)
schedule
open PMCs
(see
table 4
of this
document)
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Off- 43 (4%) 78 (22%)
schedule
open PMCs
(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, 2008)
------------------------------------------------------------------------
On-Schedule
Open PMRs NDA/ANDA (% of Total PMR) BLA (% of Total PMR)\1\
------------------------------------------------------------------------
Pending by type
------------------------------------------------------------------------
Accelerate 15 3
d
approval
------------------------------------------------------------------------
PREA\2\ 194 24
------------------------------------------------------------------------
Animal 2 0
efficacy\
3\
------------------------------------------------------------------------
FDAAA 30 12
safety
(since
March 25,
2008)
------------------------------------------------------------------------
Total 241 (79%) 39 (60%)
------------------------------------------------------------------------
Ongoing
------------------------------------------------------------------------
Accelerate 17 3
d
approval
------------------------------------------------------------------------
PREA\2\ 13 6
------------------------------------------------------------------------
Animal 0 0
efficacy\
3\
------------------------------------------------------------------------
FDAAA 0 4
safety
(since
March 25,
2008)
------------------------------------------------------------------------
Total 30 (10%) 13 (20%)
------------------------------------------------------------------------
Submitted
------------------------------------------------------------------------
Accelerate 12 2
d
approval
------------------------------------------------------------------------
PREA\2\ 9 4
------------------------------------------------------------------------
[[Page 45871]]
Animal 0 0
efficacy\
3\
------------------------------------------------------------------------
FDAAA 0 0
safety
(since
March 25,
2008)
------------------------------------------------------------------------
Total 21 (12%) 6 (9%)
------------------------------------------------------------------------
Combined 292 (95%) 58 (89%)
Total
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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, 2008)
------------------------------------------------------------------------
Off-Schedule
Open PMRs NDA/ANDA (% of Total PMR) BLA (% of Total PMR)\1\
------------------------------------------------------------------------
Delayed
------------------------------------------------------------------------
Accelerate 4 2
d
approval
------------------------------------------------------------------------
PREA 9 3
------------------------------------------------------------------------
Animal 0 0
efficacy
------------------------------------------------------------------------
FDAAA 0 0
safety
(since
March 25,
2008)
------------------------------------------------------------------------
Total 13 (4%) 5 (8%)
------------------------------------------------------------------------
Terminated 1 (0.3%) 2 (3%)
------------------------------------------------------------------------
Combined 14 (5%) 7 (11%)
total
------------------------------------------------------------------------
\1\ See note 1 for table 1 of this document.
Table 4.--Summary of On-Schedule Postmarketing Commitments (Numbers as
of September 30, 2008)
------------------------------------------------------------------------
On-Schedule
Open PMCs NDA/ANDA (% of Total PMC) BLA (% of Total PMC)\1\
------------------------------------------------------------------------
Pending 544 (54%) 112 (31%)
------------------------------------------------------------------------
Ongoing 166 (17%) 93 (26%)
------------------------------------------------------------------------
Submitted 255 (25%) 74 (21%)
------------------------------------------------------------------------
Combined 965 (96%) 279 (78%)
total
------------------------------------------------------------------------
\1\ See note 1 for table 1 of this document.
Table 5.--Summary of Off-Schedule Postmarketing Commitments (Numbers as
of September 30, 2008)
------------------------------------------------------------------------
Off-Schedule
Open PMCs NDA/ANDA (% of Total PMC) BLA (% of Total PMC)\1\
------------------------------------------------------------------------
Delayed 39 (4%) 76 (21%)
------------------------------------------------------------------------
Terminated 4 (0.4%) 2 (1%)
------------------------------------------------------------------------
Combined 43 (4%) 78 (22%)
total
------------------------------------------------------------------------
\1\ See note 1 for table 1 of this document.
Table 6.--Summary of Concluded Postmarketing Requirements and
Commitments (October 1, 2007 to October 1, 2008)
------------------------------------------------------------------------
NDA/ANDA (% of Total) BLA (% of Total)\1\
------------------------------------------------------------------------
Concluded PMRs
------------------------------------------------------------------------
Requiremen 12 (80%) 7 (70%)
t met
(fulfille
d)
------------------------------------------------------------------------
[[Page 45872]]
Requiremen 1 (7%) 0
t not met
(released
and new
revised
requireme
nt
issued)
------------------------------------------------------------------------
Requiremen 2 (13%) 3 (30%)
t no
longer
feasible
or
product
withdrawn
(released
)
------------------------------------------------------------------------
Total 15 10
------------------------------------------------------------------------
Concluded PMCs
------------------------------------------------------------------------
Commitment 94 (86%) 30 (97%)
met
(fulfille
d)
------------------------------------------------------------------------
Commitment 3 (3%) 0
not met
(released
and new
revised
requireme
nt/
commitmen
t issued)
------------------------------------------------------------------------
Commitment 12 (11%) 1 (3%)
no longer
feasible
or
product
withdrawn
(released
)
------------------------------------------------------------------------
Total 109 31
------------------------------------------------------------------------
\1\ See note 1 for table 1 of this document.
Dated: August 31, 2009.
David Horowitz,
Assistant Commissioner for Policy.
[FR Doc. E9-21302 Filed 9-3-09; 8:45 am]
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