[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:
    <bullet> 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);
    <bullet> Ongoing: The study/clinical trial is proceeding according 
to or ahead of the original schedule;
    <bullet> Delayed: The study/clinical trial is behind the original 
schedule;
    <bullet> Terminated: The study/clinical trial was ended before 
completion, but a final report has not been submitted to FDA; or
    <bullet> 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)
------------------------------------------------------------------------
  Off-                             14 (5%)                       7 (11%)
   schedule
   open PMRs
   (see
   table 3
   of this
   document)
------------------------------------------------------------------------
Number of                            1,008                           357
 open PMCs
------------------------------------------------------------------------
  On-                            965 (96%)                     279 (78%)
   schedule
   open PMCs
   (see
   table 4
   of this
   document)
------------------------------------------------------------------------
  Off-                             43 (4%)                      78 (22%)
   schedule
   open PMCs
   (see
   table 5
   of this
   document)
------------------------------------------------------------------------
\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
------------------------------------------------------------------------
\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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