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 Department of Health and Human Services Food and Drug Administration [Docket No. FDA-2009-N-0233]
 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 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 
                    ( print 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 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 § 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 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 §§ 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 §§ 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)(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 
                    ( print 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 § 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., 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 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. 
 
 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 % of Total PMC)
BLA (% of Total PMR or % of Total PMC)1Number of open PMRs
306
65On-schedule open PMRs (see table 2 of this document)
292 (95%)
58 (89%)Off-schedule open PMRs (see table 3 of this document)
14 (5%)
7 (11%)Number of open PMCs
1,008
357On-schedule open PMCs (see table 4 of this document)
965 (96%)
279 (78%)Off-schedule open PMCs (see table 5 of this document)
43 (4%)
78 (22%)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)1Pending by typeAccelerated approval
15
3PREA2
194
24Animal efficacy3
2
0FDAAA safety (since March 25, 2008)
30
12Total
241 (79%)
39 (60%)OngoingAccelerated approval
17
3PREA2
13
6Animal efficacy3
0
0FDAAA safety (since March 25, 2008)
0
4Total
30 (10%)
13 (20%)SubmittedAccelerated approval
12
2PREA2
9
4( print page 45871)Animal efficacy3
0
0FDAAA safety (since March 25, 2008)
0
0Total
21 (12%)
6 (9%)Combined Total
292 (95%)
58 (89%)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)1DelayedAccelerated approval
4
2PREA
9
3Animal efficacy
0
0FDAAA safety (since March 25, 2008)
0
0Total
13 (4%)
5 (8%)Terminated
1 (0.3%)
2 (3%)Combined total
14 (5%)
7 (11%)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)1Pending
544 (54%)
112 (31%)Ongoing
166 (17%)
93 (26%)Submitted
255 (25%)
74 (21%)Combined total
965 (96%)
279 (78%)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)1Delayed
39 (4%)
76 (21%)Terminated
4 (0.4%)
2 (1%)Combined total
43 (4%)
78 (22%)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)1Concluded PMRsRequirement met (fulfilled)
12 (80%)
7 (70%)( print page 45872)Requirement not met (released and new revised requirement issued)
1 (7%)
0Requirement no longer feasible or product withdrawn (released)
2 (13%)
3 (30%)Total
15
10Concluded PMCsCommitment met (fulfilled)
94 (86%)
30 (97%)Commitment not met (released and new revised requirement/commitment issued)
3 (3%)
0Commitment no longer feasible or product withdrawn (released)
12 (11%)
1 (3%)Total
109
311
                         See note 1 for table 1 of this document.
 Dated: August 31, 2009. David Horowitz, Assistant Commissioner for Policy.


# Footnotes

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)). Back to Citation
 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. Back to Citation
 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. Back to Citation


[FR Doc. E9-21302 Filed 9-3-09; 8:45 am] BILLING CODE 4160-01-S