[Federal Register Volume 71, Number 25 (Tuesday, February 7, 2006)]
[Notices]
[Pages 6281-6284]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-1587]



[[Page 6281]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2005N-0157]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Postmarketing Adverse 
Drug Experience Reporting

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that a 
proposed collection of information has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995.

DATES: Fax written comments on the collection of information by March 
9, 2006.

ADDRESSES: OMB is still experiencing significant delays in the regular 
mail, including first class and express mail, and messenger deliveries 
are not being accepted. To ensure that comments on the information 
collection are received, OMB recommends that written comments be faxed 
to the Office of Information and Regulatory Affairs, OMB, Attn: Fumie 
Yokota, Desk Officer for FDA, FAX: 202-395-6974.

FOR FURTHER INFORMATION CONTACT:  Karen L. Nelson, Office of Management 
Programs (HFA-250), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-1482.

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

Postmarketing Adverse Drug Experience Reporting--21 CFR 310.305 and 
314.80 (OMB Control Number 0910-0230)--Extension

    Sections 201, 502, 505, and 701 of the Federal Food, Drug, and 
Cosmetic Act (the act) (21 U.S.C. 321, 352, 355, and 371) require that 
marketed drugs be safe and effective. In order to know whether drugs 
that are not safe and effective are on the market, FDA must be promptly 
informed of adverse experiences occasioned by the use of marketed 
drugs. In order to help ensure this, FDA issued regulations at 
Sec. Sec.  310.305 and 314.80 (21 CFR 310.305 and 314.80) to impose 
reporting and recordkeeping requirements on the drug industry enabling 
FDA to take the action necessary to protect the public health from 
adverse drug experiences.
    All applicants who have received marketing approval of drug 
products are required to report to FDA serious, unexpected adverse drug 
experiences, as well as followup reports when needed (Sec.  
314.80(c)(1)). This includes reports of all foreign or domestic adverse 
experiences as well as those obtained in scientific literature and from 
postmarketing epidemiological/surveillance studies. Under Sec.  
314.80(c)(2) applicants must provide periodic reports of adverse drug 
experiences. A periodic report includes, for the reporting interval, 
reports of serious, expected adverse drug experiences and all 
nonserious adverse drug experiences, a narrative summary and analysis 
of adverse drug experiences, and a history of actions taken because of 
adverse drug experiences. Under Sec.  314.80(i), applicants must keep 
for 10 years records of all adverse drug experience reports known to 
the applicant.
    For marketed prescription drug products without approved new drug 
applications or abbreviated new drug applications, manufacturers, 
packers, and distributors are required to report to FDA serious, 
unexpected adverse drug experiences as well as followup reports when 
needed (Sec.  310.305(c)). Under Sec.  310.305(f), each manufacturer, 
packer, and distributor shall maintain for 10 years records of all 
adverse drug experiences required to be reported.
    The primary purpose of FDA's adverse drug experience reporting 
system is to provide a signal for potentially serious safety problems 
with marketed drugs. Although premarket testing discloses a general 
safety profile of a new drug's comparatively common adverse effects, 
the larger and more diverse patient populations exposed to the marketed 
drug provides, for the first time, the opportunity to collect 
information on rare, latent, and long-term effects. Signals are 
obtained from a variety of sources, including reports from patients, 
treating physicians, foreign regulatory agencies, and clinical 
investigators. Information derived from the adverse drug experience 
reporting system contributes directly to increased public health 
protection because the information enables FDA to make important 
changes to the product's labeling (such as adding a new warning) and 
when necessary, to initiate removal of a drug from the market.
    Respondents to this collection of information are manufacturers, 
packers, distributors, and applicants. FDA estimates the burden of this 
collection of information as follows:

                                                     Table 1.--Estimated Annual Reporting Burden\1\
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                                                              No. of         Annual Frequency       Total Annual        Hours per
                    21 CFR Section                         Respondents         per Response          Responses           Response         Total Hours
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310.305(c)(5)                                                           1                     1                  1                  1                  1
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314.80(c)(1)(iii)                                                       5                     1                  5                  1                  5
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314.80(c)(2)                                                          530                    20             10,600                 60            636,000
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Total                                                                                                                                            636,006
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\1\The reporting burden for Sec.  Sec.   310.305(c)(1), (c)(2), and (c)(3), and 314.80(c)(1)(i) and (c)(1)(ii) was reported under OMB control number
  0910-0291. The capital costs or operating and maintenance costs associated with this collection of information are approximately $25,000 annually.


                                                   Table 2.--Estimated Annual Recordkeeping Burden\1\
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                                                             No. of       Annual Frequency  per     Total Annual        Hours per
                    21 CFR Section                       Recordkeepers        Recordkeeping           Records          Recordkeeper       Total Hours
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310.305(f)                                                            25                      1                 25                 16                400
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314.80(i)                                                            530                      1            400,000                 16          6,400,000
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Total                                                                                                                                          6,400,400
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\1\There are no capital costs or operating costs associated with this collection of information. There are maintenance costs of $22,000 annually.

    These estimates are based on FDA's knowledge of adverse drug 
experience reporting, including the time needed to prepare the reports, 
and the number of reports submitted to the agency during 2004.
    In the Federal Register of May 3, 2005 (70 FR 22882), FDA published 
a 60-day notice requesting public comment on the information collection 
provisions (the May 2005 notice). One comment was received on the 
burden estimates.
    The comment said that it was not clear what methodology and 
assumptions were used by FDA to calculate either the annual reporting 
burden or the annual recordkeeping burden of the proposed collection of 
information.
    FDA responds that, as stated in the May 2005 notice, the estimates 
are based on FDA's knowledge of adverse dug experience reporting, 
including the time needed to prepare the reports, and the number of 
reports submitted to FDA during 2004.
    The comment said that Sec. Sec.  310.305(c)(5) and 
314.80(c)(1)(iii) in the first two rows of Table 1 in the May 2005 
notice refer to drugs without approved marketing applications and 
nonapplicants, respectively, rather than applicants. The comment 
contended that the citations used for these rows should be Sec.  
314.80(c)(1)(i) and (c)(1)(ii), which refer to the requirements for 
submission of initial and followup 15-day alert reports by the holders 
of approved marketing applications, or additional rows should be added 
to the table to include these additional reporting requirements. The 
comment also said that FDA's estimates of the burden of adverse 
experience reporting for 15-day alerts, periodic reports, and 
recordkeeping seem grossly underestimated, and that the discrepancy 
cited above concerning Sec.  314.80(c)(1)(i) and (c)(1)(ii) may account 
for the apparent underestimation of the number of respondents and 
annual frequency of responses. The comment noted that it submitted 
6,107 15-day alert reports to FDA in 2004, and that this alone exceeds 
the total burden reported in Table 1 of the May 2005 notice.
    FDA responds that the agency agrees that Table 1, as presented in 
the May 2005 notice is misleading. There is an inadvertent omission of 
the first sentence of the footnote that appears under Table 1 of the 
May 2005 notice. That footnote reads: ``There are no capital costs or 
operating and maintenance costs associated with this collection of 
information.'' The footnote should read: ``The reporting burden for 
Sec. Sec.  310.305(c)(1), (c)(2), and (c)(3), and 314.80(c)(1)(i) and 
(c)(1)(ii) was reported under OMB control number 0910-0291. There are 
no capital costs or operating and maintenance costs associated with 
this collection of information.'' (This correct version of the footnote 
appeared in earlier Federal Register notices requesting OMB extension 
of this information collection. See, for example, the Federal Register 
of July 22, 2002 (67 FR 47821)). OMB control number 0910-0291 refers to 
the information collection package for FDA's MedWatch program and forms 
(``MedWatch: Food and Drug Administration Medical Products Reporting 
Program''). The most recent request for OMB approval of this package 
was published in the Federal Register of August 16, 2005 (70 FR 48157), 
and OMB recently approved the package until October 31, 2008. MedWatch 
Form FDA 3500A is used to comply with the requirements in Sec. Sec.  
310.305(c)(1), (c)(2), and (c)(3), and 314.80(c)(1)(i) and (c)(1)(ii). 
The remaining requirements for adverse experience reporting for human 
drugs are covered in this package (OMB control number 0910-0230).
    Concerning periodic reports, the comment said the annual frequency 
per response (an estimate the comment assumed to be the average number 
of periodic reports submitted per company) is estimated by FDA to be 
20, and that this is considerably less than the 218 periodic reports 
that the comment said it submitted in 2004.
    FDA responds that the column in Table 1 of the May 2005 notice, 
entitled ``Total Annual Responses'', refers to the number of periodic 
reports submitted annually per company. FDA estimates 10,614 reports 
annually.
    The comment said that the estimate of the hours required to prepare 
each periodic report is underestimated and only seems to reflect the 
time needed to compile the report and write the narrative sections. The 
estimate does not reflect the additional time required to collect, 
prepare, solicit, and process followup information for each individual 
FDA Form 3500A report. The comment estimated that these activities take 
approximately 90 minutes for each FDA Form 3500A, and that a true 
estimate of the hours to prepare a periodic report should include at 
least an additional 1.5 hours for each non-15-day report that is 
contained within each periodic report.
    FDA responds that based on the information provided by the comment 
to prepare and submit in the periodic report information pertaining to 
15-day alert reports and non-15-day alert reports, FDA has revised the 
estimate for the time required to prepare and submit each response 
under Sec.  314.80(c)(2) to approximately 60 hours per response.
    The comment said that it does not understand how the annual 
frequency, total annual reports, and total hours are calculated for the 
estimated annual recordkeeping burden. The comment said that it needs 
to store each individual 15-day alert report, each individual non-15-
day FDA Form 3500A, and each individual periodic report. The comment 
said that FDA's estimates seem to indicate that each company has one 
document to store. The comment said that it annually submits more than 
6,000 15-day alert reports and 200 periodic reports containing many 
thousands of non-15-day FDA Form 3500As. Because of this, the comment 
said that it spends well over the one hour allotted by FDA to each 
company for these activities.
    FDA responds that the agency estimates that approximately 400,000 
records are maintained by applicants under Sec.  314.80(i). This 
estimate is based on the information provided by the comment concerning 
15-day alert reports and non-15-day alert reports, on the approximate 
number of 15-day alert reports and non-15-day alert reports received by 
FDA annually, and the fact

[[Page 6283]]

that Sec.  314.80(i) also requires that records of ``raw data and any 
correspondence relating to adverse drug experiences'' be maintained. 
FDA also estimates that approximately 16 hours are required to maintain 
each record (under Sec.  314.80(i) as well as Sec.  310.305(f)). 
Therefore, the total hours for records maintenance under Sec.  
314.80(i) is approximately 6,400,000.
    The comment disagreed with FDA's statement that there are no 
capital costs, operating, or maintenance costs associated with the 
collection of 15-day alert and periodic reports. The comment said that 
it (and other pharmaceutical companies) develop and maintain or 
purchase expensive, validated databases to collect and process adverse 
event information. These systems must continually be enhanced to 
accommodate new regulatory initiatives, such as the electronic 
submission of individual case safety reports in accordance with the 
International Conference on Harmonisation (ICH) E2B guidelines. The 
comment said that companies must purchase servers (sometimes multiple 
servers worldwide), and each employee needs hardware and software. 
Support services for these systems are also quite expensive. The 
comment also said that companies must license the Medical Dictionary 
for Regulatory Activities each year to meet the international standards 
for common reporting terminology. The comment said that costs for 
computer systems vary widely, but can amount to millions of dollars per 
year, especially for larger companies, and that capital and operational 
expenses for safety databases average $7.6 million per year. The 
comment also questioned the statement that there are no capital, 
operating, or maintenance costs associated with maintaining records of 
adverse experience reports for 10 years. The comment said that 
companies must maintain facilities to store what amounts to large 
volumes of paper records, in addition to backup records on other media 
(scanned optical images, microfilm, and so forth). The comment said 
that costs for storage and retrieval vary widely, depending on the 
volume of records, rental fees, transportation costs, and retrieval 
fees, but can be substantial (e.g., thousands of dollars per year). The 
comment said that its storage and retrieval expenses are approximately 
$22,000 per year.
    FDA responds that based on the information provided by the comment, 
FDA estimates that the capital costs or operating and maintenance costs 
associated with records maintenance is approximately $22,000 annually. 
The comment did not suggest a specific estimate for capital costs or 
operating and maintenance costs associated with reports submitted to 
FDA. FDA believes that many of the costs discussed by the comment that 
pertain to submitting reports to FDA are standard operating procedures 
for most pharmaceutical companies. However, FDA is estimating a cost of 
approximately $25,000 annually for maintenance costs resulting from the 
reporting requirements. FDA specifically requests comment on this 
estimate.
    The comment said that it is important for FDA to move quickly to 
change periodic reporting requirements to be consistent with ICH 
guidelines for periodic safety update reports. The comment said that 
this will enable companies to submit the same report to all regulatory 
authorities globally, and will decrease the burden involved with 
preparing unique periodic reports specifically for FDA. Additionally, 
for those companies who have received a waiver from FDA to submit 
periodic reports in the periodic safety update report format, the 
comment said that this would decrease the burden of adding U.S.-
specific appendices to the reports. The comment also said that periodic 
safety update reports submitted to FDA should not routinely include any 
information in addition to that included in ICH guidelines for periodic 
safety update reports. The comment noted that FDA should not require 
full copies in either paper or electronic form of cases that were not 
subject to expedited reporting. If a potential signal arises about a 
specific product, FDA has the authority and opportunity to request all 
available information associated with any individual case(s). The 
comments said that greater collaboration between FDA and companies when 
FDA identifies a potential signal would facilitate better 
pharmacovigilance. For example, case reports should be shared and 
mutually discussed.
    The comment said that electronic submission of 15-day alert reports 
would decrease the reporting burden, and that FDA requirements for 
electronic submission should be harmonized with European Agency for the 
Evaluation of Medicinal Products requirements, so pharmaceutical 
companies do not have to develop and validate separate programs.
    The comment said that cost savings could be realized by both FDA 
and companies by eliminating the requirement for submitting original 
literature articles as attachments to 15-day alert reports. Articles 
would always be available to FDA on request. Alternatively, if there 
was electronic reporting, the literature article could be submitted 
electronically as an attachment in accordance with the ICH E2B 
guidance.
    The comment said that cost savings could also be realized by 
eliminating the requirement to collect non-serious labeled events. 
Costs associated with collecting information that has little, if any, 
value has a substantial financial impact on both companies and the 
agency.
    The comment also said that it supports FDA's efforts to consider 
provisions for alternate methods of data storage other than through 
hard copy paper records. Companies prefer to choose and maintain 
methods for storage and retrieval of records according to the 
individual companies' needs. Storing scanned optical images of records 
instead of paper copies would considerably decrease the need for large 
file rooms, extensive offsite storage facilities, and the costs 
associated with maintaining these facilities.
    FDA responds that the agency is in the process of revising its 
safety reporting and recordkeeping regulations. In the Federal Register 
of March 14, 2003 (68 FR 12406), FDA proposed to amend its pre- and 
postmarketing safety reporting regulations for human drug and 
biological products to implement definitions and reporting formats and 
standards recommended by the International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human 
Use and by the World Health Organization's Council for International 
Organizations of Medical Sciences. The rulemaking is also intended to 
codify FDA's expectations for timely acquisition, evaluation, and 
submission of relevant safety information for marketed drugs and 
licensed biological products, to require that certain information be 
submitted to FDA in an expedited manner, to clarify certain 
requirements, and to make other minor revisions. FDA also proposed to 
amend its postmarketing annual reporting regulations for human drug and 
licensed biological products to revise the content for these reports. 
In the proposed rule, FDA said that it is taking this action to 
strengthen its ability to monitor the safety of human drugs and 
biological products. The intended effect of the changes would be to 
further worldwide consistency in the collection of safety information 
and submission of safety reports, increase the quality of safety 
reports, expedite FDA's review of critical safety information, and 
enable FDA to protect and promote public

[[Page 6284]]

health. FDA said that the proposed changes would be an important step 
toward global harmonization of safety reporting requirements and 
additional efforts are underway within the Department of Health and 
Human Services to harmonize the reporting requirements of U.S. Federal 
agencies (e.g., FDA and the National Institutes of Health are 
continuing to work together to address the best ways to streamline 
information sharing and to harmonize, to the extent possible, the 
safety reporting requirements of the two agencies).

    Dated: January 30, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-1587 Filed 2-6-06; 8:45 am]
BILLING CODE 4160-01-S