Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Postmarketing Adverse Drug Experience Reporting, 6281-6284 [E6-1587]

Download as PDF 6281 Federal Register / Vol. 71, No. 25 / Tuesday, February 7, 2006 / Notices DEPARTMENT OF HEALTH AND HUMAN SERVICES collection of information to OMB for review and clearance. Food and Drug Administration 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 §§ 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 (§ 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 § 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 § 314.80(i), [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. 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. 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 ADDRESSES: 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 (§ 310.305(c)). Under § 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 longterm 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 BURDEN1 21 CFR Section No. of Respondents Annual Frequency per Response Total Annual Responses Hours per Response Total Hours 310.305(c)(5) 1 1 1 1 1 314.80(c)(1)(iii) 5 1 5 1 5 530 20 10,600 60 636,000 314.80(c)(2) Total 636,006 1The reporting burden for §§ 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. erjones on PROD1PC68 with NOTICES TABLE 2.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1 21 CFR Section No. of Recordkeepers 310.305(f) VerDate Aug<31>2005 Annual Frequency per Recordkeeping 25 15:23 Feb 06, 2006 Jkt 208001 PO 00000 Frm 00033 Total Annual Records 1 Fmt 4703 Sfmt 4703 Hours per Recordkeeper 25 E:\FR\FM\07FEN1.SGM 16 07FEN1 Total Hours 400 6282 Federal Register / Vol. 71, No. 25 / Tuesday, February 7, 2006 / Notices TABLE 2.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1—Continued 21 CFR Section No. of Recordkeepers 314.80(i) Annual Frequency per Recordkeeping 530 Total Annual Records 1 Hours per Recordkeeper 400,000 16 Total erjones on PROD1PC68 with NOTICES 1There Total Hours 6,400,000 6,400,400 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 §§ 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 § 314.80(c)(1)(i) and (c)(1)(ii), which refer to the requirements for submission of initial and followup 15day 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 § 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. VerDate Aug<31>2005 15:23 Feb 06, 2006 Jkt 208001 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 §§ 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 §§ 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. PO 00000 Frm 00034 Fmt 4703 Sfmt 4703 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-15day 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 § 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-15day 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 § 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 E:\FR\FM\07FEN1.SGM 07FEN1 erjones on PROD1PC68 with NOTICES Federal Register / Vol. 71, No. 25 / Tuesday, February 7, 2006 / Notices that § 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 § 314.80(i) as well as § 310.305(f)). Therefore, the total hours for records maintenance under § 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 VerDate Aug<31>2005 15:23 Feb 06, 2006 Jkt 208001 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 15day alert reports. Articles would always be available to FDA on request. Alternatively, if there was electronic PO 00000 Frm 00035 Fmt 4703 Sfmt 4703 6283 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 E:\FR\FM\07FEN1.SGM 07FEN1 6284 Federal Register / Vol. 71, No. 25 / Tuesday, February 7, 2006 / Notices 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 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. 2006N–0045] Behavior-Based Blood Donor Deferrals in the Era of Nucleic Acid Testing; Public Workshop; Request for Comments AGENCY: Food and Drug Administration, HHS. Notice of public workshop; request for comments. erjones on PROD1PC68 with NOTICES ACTION: The Food and Drug Administration (FDA) is announcing a public workshop entitled ‘‘Behavior-Based Blood Donor Deferrals in the Era of Nucleic Acid Testing (NAT).’’ The purpose of the public workshop is to address regulatory and scientific challenges and opportunities in the development of policy concerning protection of the blood supply from transfusiontransmissible diseases by deferring blood donors based on high-risk behavior, and to request comments on this topic. Date and Time: The public workshop will be held on March 8, 2006, from 8 a.m. to 5:30 p.m. The deadline for registration via mail, fax, or e-mail is February 17, 2006 (see Registration). Written or electronic comments will be accepted until May 8, 2006 (see Comments). Addresses: The public workshop will be held at the National Institutes of Health, Lister Hill Auditorium, Bldg. 38A, 8600 Rockville Pike, Bethesda, MD 20894. Submit written comments to the Division of Dockets Management (HFA– 305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, VerDate Aug<31>2005 15:23 Feb 06, 2006 Jkt 208001 MD 20852. Submit electronic comments to https://www.fda.gov/dockets/ ecomments. Contact Person: Rhonda Dawson, Center for Biologics Evaluation and Research (HFM–302), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852–1448, 301–827– 6129, FAX: 301–827–2843, e-mail: Rhonda.Dawson@fda.hhs.gov. Registration: Mail, fax, or e-mail your registration information (including name, title, firm name, address, and telephone and fax numbers) to Rhonda Dawson (see Contact Person) by February 17, 2006. There is no registration fee for the public workshop. Early registration is recommended because seating is limited. Registration on the day of the public workshop will be provided on a space-available basis beginning at 7:15 a.m. If you need special accommodations due to a disability, please contact Rhonda Dawson (see Contact Person) at least 7 days in advance. Comments: Regardless of attendance at the public workshop, interested persons may submit to the Division of Dockets Management (see Addresses) written or electronic comments regarding the public workshop. Submit electronic comments to https:// www.fda.gov/dockets/ecomments. Submit a single copy of electronic comments or two paper copies of any mailed comments, except that individuals may submit one paper copy. Comments are to be identified with the docket number found in brackets in the heading of this document. Received comments may be seen in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday. SUPPLEMENTARY INFORMATION: The purpose of the public workshop is to address regulatory and scientific challenges and opportunities in the development of policy concerning protection of the blood supply from transfusion-transmissible diseases by deferring blood donors based on highrisk behavior. The public workshop will feature presentations by national and international experts from government and academic institutions and industry. The following discussions will be included: • Current practices in the United States and in foreign countries regarding blood donor deferrals based on high-risk behavior, • Comparison of selected tissue donor deferral policies to blood donor deferral policies, • Behavioral risks for transfusiontransmitted diseases, • Residual risks of infection from transfusion, and PO 00000 Frm 00036 Fmt 4703 Sfmt 4703 • Potential alternative approaches to donor screening and testing. Transcripts: Transcripts of the public workshop may be requested in writing from the Freedom of Information Office (HFI–35), Food and Drug Administration, 5600 Fishers Lane, rm. 12A–16, Rockville, MD 20857, approximately 15 working days after the public workshop at a cost of 10 cents per page. A transcript of the public workshop will be available on the Internet at https://www.fda.gov/cber/ minutes/workshop-min.htm. Dated: January 31, 2006. Jeffrey Shuren, Assistant Commissioner for Policy. [FR Doc. E6–1588 Filed 2–6–06; 8:45 am] BILLING CODE 4160–01–S DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Independent Evaluation of the Food and Drug Administration’s First Cycle Review Performance—Retrospective Analysis Final Report; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice of availability. SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of a report entitled ‘‘Independent Evaluation of FDA’s First Cycle Review Performance— Retrospective Analysis Final Report.’’ This report describes an independent evaluation of the issues associated with FDA’s conduct of first cycle reviews of new molecular entities for new drug applications (NMEs for NDAs), and biological license applications (BLAs). Applications covered by the report are those submitted to FDA in fiscal years 2002 to 2004. This independent study was conducted in relation to the Prescription Drug User Fee Amendments of 2002 (PDUFA III). This assessment includes a detailed evaluation of the events that occurred during the review process with a focus on identifying the best practices by FDA and industry that facilitated that process. Submit written requests for single copies of this report to the Office of Planning (HFP–10), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Send one selfaddressed adhesive label to assist that office in processing your requests. Submit electronic requests to Carolyn.Staples@fda.hhs.gov. This ADDRESSES: E:\FR\FM\07FEN1.SGM 07FEN1

Agencies

[Federal Register Volume 71, Number 25 (Tuesday, February 7, 2006)]
[Notices]
[Pages 6281-6284]
From the Federal Register Online via the Government Printing 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.

-----------------------------------------------------------------------

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\
--------------------------------------------------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual Hours per
21 CFR Section Respondents per Response Responses Response Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
310.305(c)(5) 1 1 1 1 1
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.80(c)(1)(iii) 5 1 5 1 5
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.80(c)(2) 530 20 10,600 60 636,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total 636,006
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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\
--------------------------------------------------------------------------------------------------------------------------------------------------------
No. of Annual Frequency per Total Annual Hours per
21 CFR Section Recordkeepers Recordkeeping Records Recordkeeper Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
310.305(f) 25 1 25 16 400
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 6282]]

314.80(i) 530 1 400,000 16 6,400,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total 6,400,400
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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

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