[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]
------------------------------------------------------------------------
                                  NDA/ANDA  (% of     >BLA  (% of total
                                 total PMR  or % of   PMR  or % of total
                                     total PMC)            PMC)\1\
------------------------------------------------------------------------
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)................
------------------------------------------------------------------------
\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]
------------------------------------------------------------------------
                                  NDA/ANDA  (% of      BLA  (% of total
     On-schedule open PMRs           total PMR             PMR) \1\
------------------------------------------------------------------------
Pending (by type):
    Accelerated approval......                    6                    4
    PREA \2\..................                  185                   26
    Animal efficacy \3\.......                    2                    0
    FDAAA safety (since March                    85                   35
     25, 2008)................
                               -----------------------------------------
        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)................
                               -----------------------------------------
        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)................
                               -----------------------------------------
        Total.................              36 (9%)               4 (4%)
                               -----------------------------------------
          Combined total......          372 (91.5%)             88 (92%)
------------------------------------------------------------------------
\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]
------------------------------------------------------------------------
                                  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)................
                               -----------------------------------------
        Total.................              31 (8%)              7 (12%)
                               -----------------------------------------
Terminated....................             2 (0.5%)               1 (1%)
                               -----------------------------------------

[[Page 68806]]

 
    Combined total............                   33                    8
                                             (8.5%)                 (9%)
------------------------------------------------------------------------
\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%)
                               -----------------------------------------
    Combined total............            867 (89%)           244 (75%)
------------------------------------------------------------------------
\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%)
                               -----------------------------------------
    Combined total............            111 (11%)             81 (25%)
------------------------------------------------------------------------
\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]
------------------------------------------------------------------------
                                  NDA/ANDA  (% of     BLA  (% of total)
                                       total)                \1\
------------------------------------------------------------------------
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).....
                               -----------------------------------------
        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).....
                               -----------------------------------------
        Total.................                  328                   39
------------------------------------------------------------------------
\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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