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 Department of Health and Human Services Food and Drug Administration [Docket No. FDA-2012-N-0169]
 AGENCY: Food and Drug Administration, HHS.
 ACTION: Notice of availability.
 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: Meg Pease-Fye, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 4156, Silver Spring, MD 20993-0002, 301-796-0700; or Stephen Ripley, Center for Biologics Evaluation and Research (HFM-17), Food and Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852, 301-827-6210.


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 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] 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 
                    ( print page 13340)
                    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 § 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 § 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 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 §§ 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 either 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 §§ 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 § 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 status of PMRs and PMCs as of September 30, 2011. 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] 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 § 314.81(b)(2)(vii) or § 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).
                    ( print page 13341) Many applicants have more than one approved product and for many products there is more than one PMR or PMC. Specifically, there were 175 unique applicants with 198 NDAs/ANDAs that had open PMRs/PMCs. There were 72 unique applicants with 99 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 2011 (FY11), 21 percent (43/208) of NDA/ANDA and 41 percent (41/99) 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 56 percent (23/41) of the BLA reports were submitted before the close of FY11 (September 30, 2011). Most PMRs are progressing on schedule (87 percent for NDAs/ANDAs; 88 percent for BLAs). Most PMCs are also progressing on schedule (80 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] III. About This Report This report provides six separate summary tables. The tables in this document 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, 2011. 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 (87 percent for NDAs/ANDAs and 88 percent for BLAs) and most PMCs (80 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), 92 percent were created within the past 3 years. Table 2 of this document shows that 49 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 (49 percent) comprises those studies/clinical trials required by FDA under FDAAA, which became effective on March 25, 2008. Table 3 of this document provides additional detail on the status of off-schedule PMRs. The majority of off-schedule PMRs (which account for 13 percent of the total for NDAs/ANDAs and 12 percent for BLAs) are delayed according to the original schedule milestones (98 percent (83/85) for NDAs/ANDAs; 95 percent (20/21) 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 of this document provides additional detail on the status of on-schedule PMCs. Pending PMCs comprise 48 percent (141/295) of the on-schedule NDA/ANDA PMCs and 39 percent (81/209) 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 20 percent for NDAs/ANDAs and 25 percent for BLAs) are delayed according to the original schedule milestones (93 percent (69/74) for NDAs/ANDAs; 97 percent (69/71) for BLAs). As noted previously in this document, 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. The majority of concluded PMRs and PMCs were fulfilled (70 percent of NDA/ANDA PMRs and 84 percent of BLA PMRs; 85 percent of NDA/ANDA PMCs and 80 percent of BLA PMCs). Table 1—Summary of Postmarketing Requirements and Commitments
[Numbers as of September 30, 2011]
NDA/ANDA (percent of total PMR or percent of total PMC)
BLA (percent of total PMR or percent of total PMC) 1Number of open PMRs
675
176On-schedule open PMRs (see table 2 of this document)
590 (87%)
155 (88%)Off-schedule open PMRs (see table 3 of this document)
85 (13%)
21 (12%)Number of open PMCs
369
280On-schedule open PMCs (see table 4 of this document)
295 (80%)
209 (75%)( print page 13342)Off-schedule open PMCs (see table 5 of this document)
74 (20%)
71 (25%)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, 2011]
On-Schedule open PMRs
NDA/ANDA (percent of Total PMR)
BLA (percent  of total PMR) 1Pending (by type):Accelerated approval
8
1PREA 2
238
34Animal efficacy 3
1
0FDAAA safety (since March 25, 2008)
199
72Total
446 (66%)
107 (61%)Ongoing:Accelerated approval
13
9PREA 2
35
5Animal efficacy 3
0
0FDAAA safety (since March 25, 2008)
41
23Total
89 (13%)
37 (21%)Submitted:Accelerated approval
3
2PREA 2
24
4Animal efficacy 3
0
0FDAAA safety (since March 25, 2008)
28
5Total
55 (8%)
11 (6%)Combined total
590 (87%)
155 (88%)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, 2011]
Off-Schedule open PMRs
NDA/ANDA (percent of total PMR)
BLA (percent of total PMR) 1Delayed:Accelerated approval
5
2PREA
64
12Animal efficacy
1
0FDAAA safety (since March 25, 2008)
13
6Total
83 (12%)
20 (11%)Terminated
2 (0.3%)
1 (0.6%)Combined total
85 (13%)
21 (12%)1
                         See note 1 for table 1 of this document.
 
 
 Table 4—Summary of On-Schedule Postmarketing Commitments
[Numbers as of September 30, 2011]
On-Schedule open PMCs
NDA/ANDA (percent of total PMC)
BLA (percent of total PMC) 1Pending
141 (38%)
81 (29%)Ongoing
77 (21%)
72 (26%)Submitted
77 (21%)
56 (20%)Combined total
295 (80%)
209 (75%)1
                         See note 1 for table 1 of this document.
 Table 5—Summary of Off-Schedule Postmarketing Commitments
[Numbers as of September 30, 2011]
Off-Schedule open PMCs
NDA/ANDA (percent of total PMC)
BLA (percent of total PMC) 1Delayed
69 (19%)
69 (25%)Terminated
5 (1%)
2 (0.7%)Combined total
74 (20%)
71 (25%)1
                         See note 1 for table 1 of this document.
 Table 6—Summary of Concluded Postmarketing Requirements and Commitments
[October 1, 2010 to October 1, 2011]
NDA/ANDA (percent of total)
BLA (percent of total) 1Concluded PMRs:Requirement met (fulfilled)
55 (70%)
16 (84%)Requirement not met (released and new revised requirement issued)
21 (27%)
0 (0%)Requirement no longer feasible or product withdrawn (released)
3 (4%)
3 (16%)Total
79
19Concluded PMCs:Commitment met (fulfilled)
109 (85%)
44 (80%)Commitment not met (released and new revised requirement/commitment issued)
12 (9%)
2 (4%)Commitment no longer feasible or product withdrawn (released)
7 (5%)
9 (16%)Total
128
551
                         See note 1 for table 1 of this document.
 Dated: February 28, 2012. Leslie Kux, Acting Assistant Commissioner for Policy.


# Footnotes

1.
    
                         Before passage of the Food and Drug Administration Amendments Act of 2007 (FDAAA), FDA could require postmarketing studies and clinical trials under the following circumstances: To verify adn 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 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 not adequately labeled for children under section 505B of the FD&C Act (Pediatric Research Equity Act (21 U.S.C. 355c; Pub. L. 108-155)). Back to Citation
 2.
    
                         Although the data included in this report do not include a summary of reports that applicants 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. Back to Citation
 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. Under section 505(o)(3)(c) of the FD&C Act, the Agency may convert pre-existing PMCs into PMRs if it becomes aware of new safety information. Back to Citation


[FR Doc. 2012-5302 Filed 3-5-12; 8:45 am] BILLING CODE 4160-01-P