[Federal Register: August 21, 2009 (Volume 74, Number 161)]
[Proposed Rules]
[Page 42184-42203]
[DOCID:fr21au09-10]

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Proposed Rules
                                                Federal Register
________________________________________________________________________

This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 314, and 600

[Docket No. FDA-2008-N-0334]
RIN 0910-AF96

Postmarketing Safety Reports for Human Drug and Biological
Products; Electronic Submission Requirements

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its postmarketing safety reporting regulations for human drug and
biological products to require that persons subject to mandatory
reporting requirements submit safety reports in an electronic format
that FDA can process, review, and archive. FDA is taking this action to
improve the agency's systems for collecting and analyzing postmarketing
safety reports. The proposed change would help the agency to more
rapidly review postmarketing safety reports, identify emerging safety
problems, and disseminate safety information in support of FDA's public
health mission. In addition, the proposed amendments would be a key
element in harmonizing FDA's postmarketing safety reporting regulations
with international standards for the electronic submission of safety
information.

DATES:  Submit written or electronic comments on the proposed rule by
November 19, 2009. Submit comments on information collection issues
under the Paperwork Reduction Act of 1995 by September 21, 2009, (see
section ``VII. Paperwork Reduction Act of 1995'' of this document). See
section III.G of this document for the proposed effective date of a
final rule based on this proposed rule.

ADDRESSES:  You may submit comments, identified by Docket No. FDA-2008-
N-0334 and/or RIN number 0910-AF96, by any of the following methods,
except that comments on information collection issues under the
Paperwork Reduction Act of 1995 must be submitted to the Office of
Regulatory Affairs, Office of Management and Budget (OMB) (see the
``Paperwork Reduction Act of 1995'' section of this document).
Electronic Submissions
    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Written Submissions
    Submit written submissions in the following ways:
     FAX:<PHONE_NUMBER>.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal, as described previously, in the ADDRESSES portion
of this document under Electronic Submissions.
    Instructions: All submissions received must include the agency name
and Docket No. and Regulatory Information Number (RIN) for this
rulemaking. All comments received may be posted without change to
http://www.regulations.gov, including any personal information
provided. For additional information on submitting comments, see the
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
    Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number(s), found in brackets in the heading of this document,
into the ``Search'' box and follow the prompts and/or go to the
Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville,
MD 20852.
    The information collection provisions of this proposed rule have
been submitted to OMB for review. Interested persons are requested to
fax comments regarding information collection by September 21, 2009, to
the Office of Information and Regulatory Affairs, OMB. To ensure that
comments on information collection are received, OMB recommends that
written comments be faxed to the Office of Information and Regulatory
Affairs, OMB, Attn: FDA Desk Officer, FAX:<PHONE_NUMBER>, or e-mailed to
<EMAIL_ADDRESS>
FOR FURTHER INFORMATION CONTACT:
    For information concerning human drug products: Roger Goetsch,
Center for Drug Evaluation and Research, Food and Drug Administration,
10903 New Hampshire Ave., Bldg. 22, Silver Spring, MD, 20993-0002, 301-
770-9299, or
    For information concerning human biological products: Stephen
Ripley, Center for Biologics Evaluation and Research (HFM-17), Food and
Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD,
20852-1448,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
II. Background
    A. Current Postmarketing Safety Reporting Requirements
    1. Description and Timing of Safety Reports
    2. Current Format for the Submission of Postmarketing Safety
Reports
    B. Previously Proposed Revisions to the Postmarketing Safety
Reporting Requirements
    C. Rationale for Requiring Electronic Submission of Postmarketing
Safety Reports
    1. Expedited Identification of Emerging Safety Problems
    2. Improved Speed and Efficiency of Industry and Agency Operations
    3. International Harmonization of Safety Reporting
    D. Electronic Format Submission Initiatives
    1. Electronic Submission of Postmarketing Safety Reports
    2. Comments on the Advance Notice of Proposed Rulemaking (ANPRM)
for Mandatory Electronic Submission of Postmarketing Safety Reports to
FDA
III. Description of the Proposed Rule
    A. Electronic Submission of Postmarketing Safety Reports

    B. Safety Reports Not Covered by the Proposed Rule
    C. Waivers
    D. Individual Case Safety Report (ICSR)--Definition and Required
Information
    E. Removal of Paper Format Provisions
    F. Miscellaneous Changes
    G. Proposed Implementation Timeframe
IV. Legal Authority
V. Environmental Impact
VI. Analysis of Impacts
    A. Benefits
    B. Costs
    C. Summary of Benefits and Costs
    D. Alternatives Considered
    E. Small Business Impact
VII. Paperwork Reduction Act of 1995
    A. Reporting Cost
    B. Capital Costs
VIII. Federalism
IX. Request for Comments

I. Introduction

    When a drug or biological product is approved and enters the
market, the product is introduced to a larger patient population in
settings different from clinical trials. New information generated
during the postmarketing period offers further insight into the
benefits and risks of the product, and evaluation of this information
is important to ensure the safe use of these products.
    FDA receives information regarding postmarketing adverse drug
experiences\1\ from safety reports submitted to the agency. For nearly
35 years, FDA has received these postmarketing safety reports on paper.
In recent years, many companies have voluntarily submitted these
reports to the agency in electronic format.
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    \1\ For purposes of this preamble, the term adverse drug
experience includes an adverse experience associated with use of a
biological product.
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    Data from both electronic and paper reports are entered into FDA's
Adverse Event Reporting System (AERS) database. AERS is a computerized
information database designed to support FDA's postmarketing safety
surveillance program for drug and biological products. The AERS
database is used to store and analyze data received in postmarketing
safety reports. Safety reporting data submitted on paper must first be
converted into an electronic format before being entered into AERS.\2\
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    \2\ Additional information regarding the AERS database may be
found at: http://www.fda.gov/cder/aers/default.htm.
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    FDA is proposing to require use of an electronic format for the
submission of postmarketing safety reports (see section II of this
document), which would be an important step toward improving the
agency's systems for collecting and analyzing these reports. The
proposal would:
     Eliminate the time and costs associated with submitting
paper reports (for industry) and converting data from paper reports
into electronic format for review and analysis (for the agency),
     Expedite the agency's access to safety information and
provide data to the agency in a format that would support more
efficient and comprehensive reviews, and
     Enhance our ability to rapidly communicate information
about suspected problems to health care providers, consumers,
applicants, and sponsors within the United States and internationally
in support of FDA's public health mission.
    The proposed rule would require that postmarketing safety reports
be submitted to us in an electronic format that we can process, review,
and archive. Consistent with FDA's current practice for firms that
already submit these reports in electronic format voluntarily,
technical specifications referenced in FDA guidance documents will
describe how to submit such reports to the agency.\3\ As necessary, the
agency will revise the technical specifications referenced in FDA
guidance documents to address changing technical specifications or any
additional specifications that may be needed for mandatory electronic
safety reporting. Using guidance documents to communicate these
technical specifications will permit FDA to be more responsive to
rapidly occurring changes in the technological environment.
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    \3\ The most current information on submitting postmarketing
safety reports in electronic format can be found in the draft
guidance on ``Providing Regulatory Submissions in Electronic
Format--Postmarketing Individual Case Safety Reports'' (73 FR 33436,
June 12, 2008) and the ``Periodic safety update reports'' section of
the guidance on ``Providing Regulatory Submissions in Electronic
Format--Human Pharmaceutical Product Applications and Related
Submissions Using the eCTD Specifications'' (Revision 2, June 2008).
We intend to finalize the draft guidance document in the near
future.
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    Currently, the technical specifications referenced in guidance
documents rely upon and adopt certain safety reporting and transmission
standards recommended by the International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH). ICH was formed to facilitate the harmonization of technical
requirements for the registration of pharmaceutical products among the
three ICH regions: The European Union, Japan, and the United States. In
this proposed rule, we reaffirm our intention to continue to rely on
these ICH-recommended standards, in addition to providing other options
(see section II.D.1 of this document). We believe the continued use of
ICH standards will promote harmonization of safety reporting among
regulatory agencies and facilitate the international exchange of
postmarketing safety information. Accordingly, this proposed rule is
consistent with ongoing agency initiatives to encourage the widest
possible use of electronic technology and to promote international
harmonization of safety reporting for human drug and biological
products through reliance on ICH standards. (See section II.C.3 of this
document for additional discussion of ICH.).
    In this document, we provide background information on the current
status of FDA's postmarketing safety reporting requirements (current
regulations and previously proposed revisions) (sections II.A and II.B
of this document). We also discuss the rationale for proposing this
rule (section II.C of this document). Additionally, we describe
electronic postmarketing safety reporting initiatives (section II.D of
this document), including an advanced notice of proposed rulemaking
(ANPRM) that we issued in 1998. Finally, we describe the proposed rule
(section III of this document).

II. Background

A. Current Postmarketing Safety Reporting Requirements

    The current postmarketing safety reporting requirements for drug
and biological products are summarized below. The proposed electronic
reporting amendments would leave the substantive aspects of these
requirements largely unchanged.
1. Description and Timing of Safety Reports
    Under existing regulations in part 310, 314, and 600 (21 CFR part
310, 314, and 600), specifically Sec. Sec.  310.305, 314.80, 314.98,
and 600.80, manufacturers, packers, distributors,\4\

and applicants\5\ with approved new drug applications (NDAs),
abbreviated new drug applications (ANDAs), and biological license
applications (BLAs) and those that market prescription drugs for human
use without an approved application are required to submit
postmarketing safety reports of adverse drug experiences to FDA. These
safety reports include individual case safety reports (ICSRs), and
other related documents (ICSR attachments\6\) for each adverse drug
experience. An ICSR is a description of the adverse drug experience
that includes the basic elements, or facts, of each reportable event
for an individual patient or subject. Under the current regulations,
persons who submit safety reports on paper must use the approved
reporting form for ICSRs--either the FDA Form 3500A or an equivalent
form as discussed below. Although current regulations do not use the
term ICSR, the term is used in FDA and ICH guidances to refer to the
adverse drug experience information supplied on the FDA Form 3500A or
other approved forms, including those currently submitted in electronic
format.\7\ Accordingly, we will refer throughout this document to the
description of each adverse drug experience related to an individual
patient or subject using human drug or biological products as an ICSR.
As discussed in section III.E of this document, consistent with the
proposed change to a mandatory electronic format for safety reports, we
propose to delete most references to the paper forms (e.g., FDA Form
3500A) from FDA postmarketing safety reporting regulations and to add:
(1) A definition of ICSR for drugs and biologics and (2) a statement of
the information required to be reported in an ICSR.
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    \4\ For Sec.  600.80, ``distributor'' also includes shared
manufacturers, joint manufacturers, or any other participant
involved in divided manufacturing.
    \5\ In this document, the term ``applicant'' is used instead of
the term ``licensed manufacturer'' for persons with approved BLAs.
    \6\ ICSR attachments include published articles that must
accompany ICSRs based on scientific literature (Sec. Sec.  314.80(d)
and 600.80(d)), as well as other supporting information such as
relevant hospital discharge summaries and autopsy reports/death
certificates.
    \7\ Health Level Seven (HL7), a technical-standards group
accredited by the American National Standards Institute (ANSI), also
uses the term ICSR to describe adverse event information supplied
for FDA regulated products.
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    a. 15-day Alert reports. FDA regulations require manufacturers,
packers, distributors, and applicants to submit an ICSR on FDA Form
3500A, or its equivalent, for each postmarketing adverse drug
experience that is both serious and unexpected to the agency within 15
calendar days of initial receipt of information about the adverse drug
experience (15-day ``Alert reports''). An unexpected adverse drug
experience is any adverse drug experience that is not listed in the
current labeling for the product (Sec. Sec.  310.305(b), 314.80(a), and
600.80(a)). Followup reports are required to be submitted within 15
calendar days of receipt of new information or as requested by FDA, and
are also submitted on an FDA Form 3500A or on an equivalent form. In
addition to the ICSR, 15-day Alert reports frequently include related
documents, such as medical records, hospital discharge summaries, or
other documentation related to the event (ICSR attachments).
    To avoid duplication of reports, nonapplicant manufacturers,
packers, and distributors of drug and biological products having an
approved application may, under Sec. Sec.  314.80 and 600.80, submit
all reports of serious adverse drug experiences to the applicant within
5 calendar days of receipt of the report instead of to FDA. Similarly,
packers and distributors of prescription drug products marketed without
an approved application may meet their postmarketing 15-day safety
reporting obligations under Sec.  310.305 by submitting all reports of
serious adverse drug experiences to the manufacturer within 5 calendar
days of the receipt of the information instead of to FDA. Applicants/
manufacturers receiving such data must then, in turn, submit a 15-day
Alert report to FDA.
    b. Periodic reports. In addition to 15-day Alert reports,
applicants are also required to submit postmarketing periodic safety
reports to FDA. For each approved application, applicants are required
under Sec. Sec.  314.80 and 600.80 to submit a periodic report
quarterly or annually, depending on how long the drug or biological
product has been approved. Upon written notice, the agency can require
that an applicant submit these reports to FDA at different times than
those stated. These reports contain the following information: (1) A
narrative summary and analysis of the information in the report, (2) an
analysis of all of the 15-day Alert reports submitted during the
reporting interval, (3) an ICSR (and ICSR attachments, if applicable)
for each adverse drug experience not previously reported (i.e., reports
of all serious, expected (labeled) and nonserious events)\8\, and (4) a
history of actions taken since the last periodic report because of the
reports of adverse drug experiences. The descriptive information
portions of a postmarketing periodic safety report (report summary,
analysis of 15-day Alert reports, and history of actions) are submitted
to the agency in a narrative format accompanied by the ICSRs and any
ICSR attachments for all serious, expected and nonserious adverse drug
experiences that occurred during the reporting period. Manufacturers of
drugs marketed without an approved application (e.g., NDA, ANDA) are
not required to submit postmarketing periodic safety reports to FDA.
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    \8\ In some cases, applicants may request a waiver for
submission of an ICSR for nonserious, expected adverse drug
experiences. See section XI.A of FDA's draft guidance for industry
on ``Postmarketing Safety Reporting for Human Drug and Biological
Products Including Vaccines'' available on the Internet at http://
www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
default.htm under ``Procedural.''
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    c. Distribution reports. In addition to periodic reports, under
Sec.  600.81, applicants with approved BLAs are also required to submit
distribution reports to the agency every 6 months or at other intervals
that the agency may specify with written notice. These reports contain
information about the quantity of biological product distributed under
the BLA, including the quantity distributed to distributors.
    d. Nonprescription human drug products marketed without an approved
application. Public Law 109-462, enacted on December 22, 2006, amended
the Federal Food, Drug, and Cosmetic Act (the act) to create a new
section 760 (21 U.S.C. 379aa), entitled ``Serious Adverse Event
Reporting for Nonprescription Drugs.'' Section 760 of the act requires
manufacturers, packers, or distributors whose name appears on the label
of nonprescription human drug products marketed without an approved
application to report serious adverse events associated with their
products. Effective December 22, 2007, section 760 of the act requires
these reports to be submitted to FDA within 15 business days. As
required by section 2(e)(3) of Public Law 109-462, FDA issued a draft
guidance for industry entitled ``Postmarketing Adverse Event Reporting
for Nonprescription Human Drug Products Marketed without an Approved
Application'' (72 FR 58316, October 15, 2007). The draft guidance
describes the minimum data elements and the relevant policies and
procedures for making these reports under section 760 of the act. It
provides, among other things, that the reports be submitted on paper on
FDA Form 3500A or in the electronic format described in the guidance.
    This proposed rule does not contain language that would require
that safety reports under section 760 of the act for nonprescription
human drug products marketed without an approved application be
submitted to FDA in electronic format. However, we are soliciting
public comment on whether the final rule should require the use of
electronic format for these reports. We expect that any electronic
format requirements for these section 760

reports would be quite similar to the requirements for other categories
of drug products addressed by this rule. Any decision whether to
include section 760 reports will be informed by the public comments
submitted in response to this proposal and the agency's experience
since submission of serious adverse event reports for nonprescription
human drug products marketed without an approved application became
mandatory in December 2007.
    Finally, note that nonprescription drugs that are marketed under
approved applications (NDAs or ANDAs) are not covered under section 760
of the act. Such products are subject to reporting under current
Sec. Sec.  314.80 and 314.81. Reports submitted to FDA under those
sections would be subject to the mandatory electronic format
requirements proposed in this rule as described elsewhere in this
document.
2. Current Format for the Submission of Postmarketing Safety Reports
    a. Drug and biological products. FDA currently accepts all
postmarketing ICSRs in either a paper format or an electronic format.
Sections 310.305(d), 314.80(f), and 600.80(f) authorize use of a paper
FDA Form 3500A for reporting of single cases of adverse drug
experiences for human drug and biological products. The regulations
also permit use of the form introduced by the World Health
Organization's (WHO's) Council for International Organizations of
Medical Sciences (CIOMS) Working Group I for reporting single cases of
foreign adverse drug experiences that are serious and unexpected (CIOMS
I form).
    Section 11.2(b)(2) currently provides that regulatory submissions
may be voluntarily provided to the agency in electronic form\9\ if the
submissions are identified by FDA in its electronic submissions public
docket as submissions the agency will accept in electronic form.\10\
Postmarketing safety reports for drug and nonvaccine biological
products have been identified in the docket as submissions the agency
can accept in electronic format. See Memorandums 23 and 28 in FDA's
electronic submissions public docket. If the reporter elects to file
the safety report in electronic format rather than on paper, current
Sec. Sec.  310.305(d), 314.80(f), and 600.80(f) require that the ICSRs
in the electronic report include the same information as the paper FDA
Form 3500A or CIOMS I form.
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    \9\ The content of labeling for NDAs, certain BLAs, ANDAs,
annual reports, and supplements is currently the only regulatory
submission required to be submitted to the agency electronically (68
FR 69009, December 11, 2003).
    \10\ Docket No. FDA-1992-S-0039 (formerly Docket No. 1992S-0251)
can be accessed on the Internet at http://www.regulations.gov.
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    Accordingly, under current regulations, an ICSR submission can take
the form of a paper FDA Form 3500A, a paper CIOMS I form, or comparable
information submitted in electronic format. (See section II.D.1 of this
document). Each of these is a different method of transmitting to FDA
the same basic elements of the ICSR, whether on paper or in electronic
format. As described in section II.D.1.a of this document, ICSR
attachments and the descriptive information portions of periodic safety
reports may also be submitted electronically.
    b. Vaccine products. Adverse experience reporting for vaccine
products may be submitted to the Vaccine Adverse Event Reporting System
(VAERS). VAERS is a computerized information database designed to
support the Centers for Disease Control and Prevention's (CDC's) and
FDA's postmarketing surveillance program for vaccine products.
Postmarketing ICSRs for vaccines can be submitted on a VAERS paper
form\11\ or reported on-line using the VAERS secure web-based
system\12\. Each of these is a different method of transmitting to CDC/
FDA the same basic elements of the ICSR. Currently, VAERS does not have
the capability to receive electronic ICSRs submitted through the FDA's
electronic submissions gateway. However, developments are underway to
implement this submission capability.
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    \11\ The VAERS form can be accessed on the Internet at http://
secure.vaers.org/vaersdataentryintro.htm. FDA has verified the Web
site addresses throughout this document, but FDA is not responsible
for any subsequent changes to the Web sites after this document
publishes in the Federal Register.)
    \12\ Report on-line at https://secure.vaers.org.
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B. Previously Proposed Revisions to the Postmarketing Safety Reporting
Requirements

    In the Federal Register of March 14, 2003 (68 FR 12406), FDA
published a proposed rule to amend its safety reporting requirements
for human drug and biological products (Safety Reporting Proposed
Rule). The agency proposed new definitions and reporting formats and
standards for pre- and postmarketing safety reporting as recommended by
ICH (see section II.C.3 of this document) and by CIOMS. Some of the
proposed amendments were based on the recommendations of ICH, while
others were proposed by the agency on its own initiative. With regard
to coding of postmarketing ICSRs to standardize safety reports for
comparison and analysis, the agency proposed use of the Medical
Dictionary for Regulatory Activities (MedDRA) terminology developed by
ICH\13\. The agency also proposed to require the submission of new
types of postmarketing safety reports to FDA. FDA is currently
considering the comments that it has received on the Safety Reporting
Proposed Rule. Any new postmarketing safety reports that are required
by a safety reporting final rule would be required to be submitted
electronically in accordance with this rulemaking, if adopted as final.
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    \13\ MedDRA is a medically validated medical terminology created
by ICH as a cooperative effort between the pharmaceutical industry
and regulators from the United States, Europe, and Japan for sharing
regulatory information for human medical products and activities
(see www.ich.org/cache/compo/276-254-1.html). MedDRA establishes a
terminology database for use in the regulatory process for medical
products and has become the accepted standard for regulatory
activities involving adverse drug experiences. Use of MedDRA would
serve the public health by facilitating the collection,
presentation, and analysis of adverse drug experience information
from medical products during clinical and scientific reviews and
marketing.
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C. Rationale for Requiring Electronic Submission of Postmarketing
Safety Report

    As explained more below, the agency proposes to require that all
postmarketing safety reports for human drugs and biological products be
submitted in electronic format. By requiring submission of these
reports in electronic format, FDA would expedite access to safety
information and facilitate international harmonization and exchange of
this information. This, in turn, would lead to more efficient reviews
of safety data and enhance our ability to rapidly disseminate safety
information to health care providers, consumers, applicants, sponsors,
and other regulatory authorities in support of FDA's public health
mission. In addition, the agency would recognize a significant cost
savings by converting the safety reporting system from a paper
submission process to an all electronic system that would increase the
accuracy of information and reduce the need for manual data entry.
1. Expedited Identification of Emerging Safety Problems
    Establishment and maintenance of efficient risk management programs
(where appropriate) is an agency priority (see FDA's January 2007
response to the Institute of Medicine (IOM) report on drug safety
entitled ``The Future of Drug Safety: Promoting and Protecting the
Health of the Public,''

FDA's March 2005 guidance for industry entitled ``Development and Use
of Risk Minimization Action Plans,'' and FDA's 2007 Strategic Action
Plan).\14\ The changes proposed in this rule, if adopted, would improve
the agency's management of risks from human drug and biological
products by expediting the postmarketing identification and
communication of emerging safety information for these products.
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    \14\ These resources are available on the Internet at (IOM
response) http://www.fda.gov/downloads/drugs/drugsafety/
postmarketingdrugsafetyinformationforpatientsandproviders/
UCM171627.pdf, (strategic plan) http://www.fda.gov/ope/stratplan07/
stratplan07.htm, and (guidance) http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/default.htmunder
``Clinical/Medical.''
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    Requiring that postmarketing ICSRs be submitted in electronic
format would result in reducing the time required for FDA to enter
information from a paper safety report into a database for evaluation
and analysis. Currently, approximately 60 percent of all ICSRs (i.e.,
15-day Alert reports and ICSRs associated with periodic reports\15\)
are submitted to FDA on paper for input into the AERS database
(approximately 30,000/month). With regard to 15-day Alert reports,
approximately one-third are submitted on paper (approximately 8,000/
month) to FDA. Fifteen-day Alert reports that are submitted on paper
generally reach FDA's data entry contractor within the required 15 days
following the adverse drug experience, but then the ICSRs must be
manually entered into the AERS database. These ICSRs are entered into
the FDA AERS database on a priority basis because they may indicate a
new, previously unidentified risk. The time required for data entry,
validation, and quality control processes, however, adds an additional
2 weeks before the ICSRs are actually available for assessment by FDA's
safety evaluators. With regard to periodic ICSRs, approximately 80
percent are submitted on paper (approximately 22,000/month).\16\
Periodic ICSRs, which are submitted on paper, may not be available for
review by safety evaluators for up to 2 months after submission to the
agency because of their volume and because ICSRs in 15-day Alert
reports must take first priority.
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    \15\ See section II.A.1.b of this preamble for a description of
periodic ICSRs.
    \16\ Postmarketing periodic reports are required to be submitted
to the FDA for each approved NDA, ANDA, and BLA and are due
quarterly for the first 3 years after U.S. approval of the
application and annually thereafter. An ICSR in a periodic safety
report includes the same elements in the same format as an ICSR in a
15-day Alert report, but describes an adverse drug experience that
is not both serious and unexpected (i.e., all nonserious adverse
drug experiences or serious, expected adverse drug experiences).
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    In contrast, the ICSRs in both 15-day Alert and periodic reports
submitted in electronic format are processed and available for safety
evaluator review much more quickly because there is no need for data
entry and the associated quality control and validation processes are
faster. Instead of 2 months for periodic ICSRs or 2 weeks for 15-day
Alert ICSRs that are submitted in a paper format, ICSRs submitted in
electronic format are, generally, available to reviewers within 2 days
of their receipt by FDA. The requirement for electronic safety reports
is expected to result in faster processing and this will permit FDA to
more quickly identify emerging safety issues and rapidly disseminate
significant safety information to the medical community and the public
with corresponding benefits to the public health.
2. Improved Speed and Efficiency of Industry and Agency Operations
    The proposed electronic formatting requirements for postmarketing
safety reports would enhance operations for both industry and FDA.
Electronic reporting can benefit industry by eliminating the costs
associated with collating, copying, storing, retrieving, and mailing
paper copies. In addition, FDA would benefit from the elimination of
data entry processes and significant reduction in physical storage
requirements. When data are provided only on paper, the information
must be converted manually into an electronic form to review and
analyze. This process is time consuming, costly, and creates an
opportunity for data entry error to occur.
    FDA expects to provide two options for submitting electronically
formatted ICSRs. Reporters would be able to submit ICSRs by using
either an ICH-compatible electronic transmission system, or a Web-based
form similar to those used for commercial transactions, such as retail
purchases, on the Internet. (These options, as well as those for
submission of ICSR attachments in electronic form, are discussed in
more detail in section II.D.1 of this document.) For companies that
submit large numbers of ICSRs, use of the ICH-compatible system for
electronic transmission would be cost effective because the information
from the ICSRs will be transmitted directly from the company's database
to FDA without needing additional administrative support for manual
entry of the information. For companies that submit a small number of
ICSRs, use of the Web-based form may be more cost effective than using
the ICH-compatible system.
    FDA has worked with industry on electronic submission of
postmarketing ICSRs since 1998. In 2001, FDA announced through public
docket number 92S-0251 that the agency would accept voluntary
electronic submissions of ICSRs for 15-day Alert and periodic safety
reports in lieu of a paper submission (see section II.A.2 of this
document). Currently, over 40 pharmaceutical companies are voluntarily
using electronic format to submit to FDA ICSRs for both 15-day Alert
and periodic reports for human drug and biologics, with more than
500,000 ICSRs submitted to date. This experience has shown that
electronic data submissions to the AERS database reduce the cost of
data entry and facilitate the review process. It currently costs FDA
approximately $35 to process a report submitted on paper. In
comparison, a report submitted in an electronic format costs
approximately $12 to process.
3. International Harmonization of Safety Reporting
    In developing this proposal, FDA considered the international
standards developed by ICH for the submission of safety information.
The other ICH regions (the European Union (EU) and Japan) are also
implementing the standards recommended by ICH for the electronic
submission of safety reports. The procedures for the electronic
submission of postmarketing safety reports in this proposed rule would,
therefore, reduce costs to industry associated with maintaining
multiple electronic systems designed to meet the needs of different
regulatory authorities. The proposed electronic safety reporting
regulations would also encourage better communication between FDA and
the industry, as well as with other regulators, nationally and abroad,
while reducing the costs associated with reporting. Moreover, the
industry would be able to rely on one form of electronic reporting,
which would reduce the administrative costs of compliance.
     a. Status of electronic submissions in the EU. The European
Commission drafted guidance on adverse event reporting, including
Volume 9 of ``The Rules Governing Medicinal Products in the European
Union'' (the EU rules), which contains a specific emphasis on
pharmacovigilance. The EU rules require the electronic submission of
adverse event reports (effective November 2005) and incorporate
international guidelines reached within the framework of the ICH. The
EU rules specify that the electronic transmission

and management of safety reports will be carried out according to the
guidelines and specifications contained in ICH guidance on safety
reporting and electronic standards.
    b. Status of electronic submissions in Japan. On October 27, 2003,
the Japanese Ministry of Health, Labour, and Welfare mandated that ICH
guidance E2BM\17\ compliant ICSRs be submitted in electronic format
either by the Internet or by physical media.
---------------------------------------------------------------------------

    \17\ ICH first issued guidance on ``E2B Data Elements for
Transmission of Individual Case Safety Reports'' in July 1997 (ICH
E2B). ICH E2B was revised in 2000 to include adjustments based on
successful pilot projects conducted in the three ICH regions (ICH
E2BM). ICH is currently revising its E2B guidance again to provide
additional information and clarification and has released ICH E2B(R)
in draft. The term ``ICH E2B guidance'' used in this document
includes all ICH guidance on the E2B topic of data elements for the
transmission of ICSRs. The guidances are available on the Internet
at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/default.htm under the ICH--Efficacy category or http://
www.fda.gov/cber/guidelines.htm under the ICH guidance documents
category.
---------------------------------------------------------------------------

    c. Global impact of a standard electronic submission. FDA
collaborates with many international regulatory counterparts on drug
safety issues. Frequently, FDA sends to and receives from other
regulators paper copies of ICSRs for further clinical analysis of
specific drug safety issues. FDA envisions that regulatory partners
participating in ICH, and other regulators that choose to implement the
same standards, will be able to electronically exchange specific ICSRs
in real time as safety issues emerge. As a result, regulatory partners
would be assured that they are making regulatory decisions based on a
full complement of available information.

D. Electronic Format Submission Initiatives

1. Electronic Submission of Postmarketing Safety Reports
    a. Voluntary electronic submissions. In the Federal Register of
March 20, 1997 (62 FR 13430), FDA published a regulation on electronic
records and electronic signatures (21 CFR part 11). In August 2003, FDA
issued guidance for industry entitled ``Part 11, Electronic Records;
Electronic Signatures--Scope and Application,'' describing the agency's
thinking regarding part 11. Part 11 generally provides that in
instances where records are submitted to the agency, such records may
be submitted in electronic format instead of paper format, provided
that FDA has identified the submission in FDA's electronic submissions
public docket as the type of submission that FDA can accept in
electronic format. Postmarketing safety reports have been identified in
FDA's electronic submissions public docket as submissions that FDA may
accept in electronic format\18\.
---------------------------------------------------------------------------

    \18\ Docket No. FDA-1992-S-0039 (formerly Docket No. 1992S-0251)
can be accessed on the Internet at http://www.regulations.gov.
---------------------------------------------------------------------------

    Presently, FDA allows applicants, manufacturers, packers, and
distributors to submit postmarketing safety reports (both 15-day Alert
and periodic reports) in electronic format by sending the reports to
FDA either: (1) Through FDA's Electronic Submission Gateway (ESG) or
(2) on physical media, e.g., CD-ROM, digital tape, or floppy disk (sent
by mail).\19\ These electronic submissions may include ICSRs, any ICSR
attachments, and descriptive information. The data elements and
electronic transport formats that FDA can accept for electronic ICSRs
are described in technical specifications referenced in FDA guidance
documents.\20\ Currently, FDA can accept attachments to ICSRs and the
descriptive information of periodic reports in an electronic form as
portable document format (PDF) files, which may be sent through the
FDA's ESG or mailed to FDA on physical media.\21\ To send these reports
by FDA's ESG, a manufacturer/applicant must initially contact FDA's
AERS electronic submission coordinator\22\ to establish an ESG
connection with FDA's network.
---------------------------------------------------------------------------

    \19\ FDA expects that, in the future, all electronic submissions
to the agency will be sent through the ESG and that use of physical
media for such submissions will, eventually, be phased-out.
    \20\ FDA is currently accepting electronic submissions using
either the ICH E2B or ICH E2BM data elements; ICH E2B and ICH E2BM
are available on the Internet at http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/default.htm under
the ICH--Efficacy category or http://www.fda.gov/cber/guidelines.htm
under the ICH guidance documents category.
    \21\ See footnote number 19 in this document.
    \22\ FDA's AERS electronic submission coordinator may be
contacted at<EMAIL_ADDRESS>---------------------------------------------------------------------------

    b. ICH standards. FDA codes and analyzes electronic submissions of
safety information received via the ESG or on physical media based on
ICH standards.\23\ ICH has developed international standards for the
electronic submission of safety information that include: (1)
Standardized common data elements for transmission of ICSRs (ICH E2B
guidance), and (2) electronic standard transmission procedures (ICH
M2\24\ ). ICH E2B guidance provides standardized common data elements
for the transmission of ICSRs by identifying and defining the data
elements for the transmission of all types of ICSRs, regardless of
source and destination. The ICH format for ICSRs includes provisions
for transmitting all the relevant data elements useful to assess an
individual adverse drug reaction or adverse event report. The common
data elements are sufficiently comprehensive to cover complex reports
from most sources, different data sets, and different transmission
requirements.
---------------------------------------------------------------------------

    \23\ See www.ich.org/cache/compo/276-254-1.html.
    \24\ ICH M2 provides electronic standards for the transfer of
regulatory information (ESTRI). The M2 ESTRI recommendations
facilitate international electronic communication in the three ICH
regions. The ICH M2 working group developed a specification for the
implementation of E2B data elements that allows for the transmission
of all types of ICSRs, regardless of source and destination. ICH M2
recommendations are revised periodically to reflect the evolving
nature of the technology. More information on M2 ESTRI is available
on the Internet at http://estri.ich.org.
---------------------------------------------------------------------------

    c. FDA Web-based submission portal. In addition to submission of
ICSRs through the ESG, FDA is developing a Web-based electronic
submission portal to collect and process safety information for all
FDA-regulated products that will be consistent with ICH standards and
may be used as another method for reporting adverse drug experiences to
the agency.\25\ FDA's Web-based portal will allow for the secure
electronic submission of postmarketing ICSRs directly into FDA's AERS
database once information is typed into a Web-based electronic form.
Users will receive electronic confirmation that their submissions have
been received by FDA. Any person who is subject to FDA's postmarketing
safety reporting requirements and has Internet access will be able to
use the Web-based form to submit ICSRs to the agency. The Web-based
submission function will assist entities that submit a small number of
safety reports by creating a simpler and more efficient mechanism for
reporting that does not require them to have an internal database that
is compatible with the ICH-based system. However, because some
administrative support would be needed to manually enter the
information for the ICSRs onto a form on the Web, this Web-based
electronic reporting format will be less cost effective than direct
submission through the ESG (or submitting the information on physical
media) for companies with large numbers of safety reports. As soon as
FDA can accept submissions using this Web-based form, information in
docket 92S-0251, and the guidance documents described in this section
will be updated to reflect this option.
---------------------------------------------------------------------------

    \25\ The Web-based reporting portal is based on the HL7
Individual Case Safety Report standard accredited by ANSI. This
standard is for the exchange of adverse event information between
computer systems.

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

2. Comments on the Advance Notice of Proposed Rulemaking (ANPRM) for
Mandatory Electronic Submission of Postmarketing Safety Reports to FDA
    In the Federal Register of November 5, 1998 (63 FR 59746), FDA
issued an ANPRM describing the agency's plans to require electronic
submission of all postmarketing expedited and periodic ICSRs. In the
ANPRM, the agency indicated that it would propose that international
standards be used for electronic safety reporting (i.e., precoding of
ICSRs using the ICH M1 international medical terminology, ICH E2B
format, and ICH M2 transmission specifications).\26\ FDA also indicated
that it was considering requiring that the textual (descriptive)
information contained in a postmarketing periodic safety report be
submitted to the agency in an electronic format. FDA received comments
on the ANPRM from 11 representatives of pharmaceutical companies and
associations and one individual. The agency considered these comments
in developing this proposed rule on electronic submission of
postmarketing safety reports.
---------------------------------------------------------------------------

    \26\ The proposal to require coding of ICSRs using MedDRA (ICH
M1) is included in a separate rulemaking, the Safety Reporting
Proposed Rule, described in section II.B of this document.
---------------------------------------------------------------------------

    a. General. In general, the comments supported FDA's plans to
require electronic submission of postmarketing safety reports, while a
few comments said that electronic submissions to the agency should
remain voluntary. One comment said that FDA's goal of having all safety
reports submitted in an electronic format would be realized without
being mandated as electronic record collection, retrieval, and
reporting becomes the generally-recognized norm throughout the
pharmaceutical and biologics industry.
    FDA believes that the electronic submission of postmarketing safety
reports should be required and not voluntary because, although we have
accepted the voluntary submission of postmarketing safety reports in
electronic format since 2001, we are only receiving approximately 40
percent of ICSRs in electronic format. To expedite the identification
of emerging safety problems and to realize cost savings for industry
and the agency, we will need to receive close to 100 percent of ICSRs
in electronic format.
    b. Waivers. Several comments provided suggestions for waivers
(exemptions) from the requirement to submit postmarketing safety
reports electronically to FDA. The comments described two types of
waivers: (1) Temporary hardship waivers and (2) indefinite waivers.
    Two comments requested that FDA grant a temporary hardship waiver
for companies that experience unanticipated technical difficulties
after implementation of the regulation. In this case, the company would
be permitted to submit safety reports in a paper format. One comment
said that such temporary waivers must be automatic so that regulatory
requirements for timely reporting are fulfilled. The comments said that
temporary waivers should be evaluated on an individual basis, taking
into account factors such as company size, volume of reports, potential
issues with international affiliates, and scope of required technical
activities. One comment requested that the waiver be renewable for a 6-
month period as long as the company can demonstrate progress towards
the ability to submit reports electronically.
    With regard to indefinite waivers, four comments said that small
businesses should be exempt from the requirement to submit
postmarketing safety reports in electronic format. The comments said
that a waiver should be based on the number of safety reports that a
company submits to FDA. They noted that the number of safety reports
can vary significantly among manufacturers based on such attributes as
company size and product line. One comment said that generic, or other,
drug companies that receive few adverse event reports (e.g., 0-5
adverse drug reactions (ADRs) per week) should be exempt from the
requirement. The comment stated that compliance with the requirement
would place an undue burden on these drug companies because of the
associated costs for human resources, equipment, software requirements,
and other costs. The comment further stated that if the agency does not
create a waiver for drug companies that have few ADRs per week (e.g.,
less than 5), then a longer transition period should be permitted,
during which the agency would accept either paper or electronic ADRs.
The transition period would allow sufficient time for drug companies
that currently do not have the appropriate resources to establish
electronic safety reporting systems. Another comment said that the
criterion for an automatic waiver could be limited to NDAs for products
with orphan-designated indications, because of the small number of ADRs
submitted for these products. The comment also suggested that drug
product sponsors who make less than a particular monetary amount for
drug product sales per year (e.g., $100 million) should be exempt from
the rule.
    Since these comments on the ANPRM were submitted in 1998, Internet
access has become commonplace, reducing or eliminating implementation
concerns for smaller firms or firms with very few reports. These firms
will be able to use the Web-based form. Accordingly, we are not
proposing indefinite waivers from implementation of electronic format
submission of safety reports.
    With regard to temporary waivers, we believe they should only be
necessary in rare cases. Larger companies using the ESG could use
submission on physical media (i.e., CD-ROM) or the Web-based system as
a back-up if they experience temporary technological problems with
their ESG submission system. Similarly, smaller firms regularly
reporting on the Web-based system could easily find alternative
Internet access in the event of a temporary Internet outage at the
firm. Given that it is not possible to anticipate all the various
situations that might require a waiver, we are proposing in this rule
to provide for a temporary waiver of the electronic format submission
requirement for good cause shown (see section III.C of this document).
As discussed more below, we are specifically requesting comments in
this rule on what would constitute ``good cause'' for a temporary
waiver of the electronic format submission requirements.
    c. Textual materials. ICSRs are often accompanied by textual
materials (ISCR attachments), such as hospital discharge summaries or
other medical records, published studies, or autopsy reports. Two
comments supported the possibility of submitting textual materials
electronically in addition to ICSRs. One of the comments recommended
that the electronic transmission of textual materials be accepted using
ICH standards so that consistency could be enhanced worldwide.
    As recommended in the technical specifications referenced in
guidances on submitting postmarketing safety reports in electronic
format, textual materials can currently be submitted in a paper format
or in an electronic format as a PDF file consistent with ICH
guidelines.\27\ When finalized, this rule would require submission of
these textual materials in an electronic format we can process, review,
and archive. Future changes to technical specifications for such
submissions, such as transmission standards and file formats, would be
announced in the technical specifications referenced in FDA guidance
documents.
---------------------------------------------------------------------------

    \27\ See footnote number 3 of this document.

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

    d. Security issues. Several comments discussed security issues
related to the confidentiality of data when safety reports are
submitted electronically. Some comments stated that industry and the
agency must be prepared to respond promptly to changing technology to
ensure secure transmission of data. Another comment requested that the
tools used for this purpose be commercially available at a reasonable
cost.
    The agency requires the secure transmission of all electronic
submissions. We currently have certificate authority with standard
encryption and will continue to use this security method in the
agency's ESG for the electronic submission of postmarketing safety
reports. The ESG meets National Institute of Standards and Technology
(NIST)-800\28\ series security certification standards.
---------------------------------------------------------------------------

    \28\ NIST, a nonregulatory Federal agency in the U.S. Commerce
Department's Technology Administration, promotes U.S. innovation and
industrial competitiveness by advancing measurement science,
standards, and technology, including researching and developing test
methods and standards for emerging and rapidly changing information
technologies.
---------------------------------------------------------------------------

III. Description of the Proposed Rule

    As noted previously, the changes proposed in this rule would,
largely, affect the form in which postmarketing safety reports must be
submitted to FDA (i.e., in electronic format instead of a paper format)
and, in addition, make minor conforming changes to the regulations.

A. Electronic Submission of Postmarketing Safety Reports

    The proposal would revise Sec. Sec.  310.305, 314.80, 314.98, and
600.80 to require that manufacturers, packers, and distributors, and
applicants with approved NDAs, ANDAs, and BLAs and those that market
prescription drugs for human use without an approved application submit
postmarketing safety reports to the agency in an electronic format that
FDA can process, review, and archive. We are proposing to delete the
specific references to paper reporting forms in Sec. Sec.  310.305,
314.80, and 600.80. We also propose to add language to these sections
which states that FDA will periodically issue guidance on how to
provide the electronic submissions (e.g., method of transmission,
media, file formats, preparation and organization of files).
    Postmarketing 15-day Alert and periodic reports, including the
ICSRs, any ICSR attachments and the descriptive information portion of
postmarketing periodic safety reports, would be submitted to FDA in an
electronic format. Information on the agency's ability to process,
review, and archive these reports is described in the technical
specifications referenced in FDA guidance documents (see section I of
this document). The reports would be submitted to FDA in an electronic
format only; paper copies would not be accepted unless the agency
granted a temporary waiver (see section III.C of this document).
    Under the proposed rule, for marketed products with an approved
application, manufacturers, packers, or distributors that do not hold
the application would continue to have the option of submitting 15-day
Alert reports directly to FDA or to the application holder under
Sec. Sec.  314.80(c)(1)(iii) and 600.80(c)(1)(iii). If they opt to
submit directly to FDA, they would be required to do so in electronic
format. If they choose to report to the applicant, they could submit
the report in any acceptable format. The applicant, however, would be
required to use electronic reporting when it subsequently reports the
information to FDA. Similarly, for marketed drug products without an
approved application, initial safety reports made to the manufacturer
by packers and distributors under current Sec.  310.305(c)(3) could be
made in any form agreeable to the reporter and the manufacturer, but
this proposal would require all safety reports made to FDA to be made
in electronic format.
    This proposal applies to all postmarketing safety reports currently
required to be submitted to FDA under Sec. Sec.  310.305, 314.80,
314.98, and 600.80 (including vaccines) and would apply to any new
postmarketing safety reports for drug or biological products that are
implemented in the future (e.g., new postmarketing safety reports
proposed in the Safety Reporting Proposed Rule described in section
II.B of this document). The proposal would also revise Sec.  600.81 by
requiring the electronic submission of biological lot distribution
reports. As previously described for postmarketing safety reports, FDA
will also periodically issue guidance on how to provide the electronic
submissions for these reports (e.g., method of transmission, media,
file formats, preparation and organization of files).

B. Safety Reports Not Covered by the Proposed Rule

    Postmarketing safety reports for drugs, including vaccines,
constitute the largest volume of paper safety reports received by the
agency and, consequently, require the most resources to input
electronically. This proposed rule would permit more efficient
management of these postmarketing safety reports by FDA. This proposed
rule would not apply to submission of the following safety reports:
     Investigational new drug application (IND) safety reports
(Sec.  312.32);
     Safety update reports for drugs (Sec.
314.50(d)(5)(vi)(b));
     Approved NDA and BLA annual reports (Sec. Sec.
314.81(b)(2) and 601.28 (21 CFR 601.28));
     Biological product deviation reports (BPDRs) (Sec. Sec.
600.14 and 606.171 (21 CFR 606.171));
     Reports of complications of blood transfusion and
collection confirmed to be fatal (21 CFR 606.170(b) and 640.73);
     Adverse reaction reports for human cells, tissues and
cellular and tissue-based products (HCT/Ps) regulated solely under
section 361 of the Public Health Service Act (42 U.S.C. 264) (21 CFR
1271.350(a)); and
     NDA-field alert reports (Sec.  314.81(b)(1)).
    We have not proposed to require that premarketing safety reports be
submitted electronically because IND safety reports are submitted
directly to the review division with responsibility for the IND, and
are not uploaded into the AERS database. Blood transfusion and
collection fatality reports are submitted to the agency in lower
numbers than the postmarketing safety reports addressed in this rule;
therefore, we have not proposed that these reports be subject to the
mandatory electronic format requirements proposed in this rule. The
agency has not yet received blood transfusion and collection fatality
reports as electronic submissions, but does receive BPDRs through a
voluntary electronic submission process. We are considering a mandatory
electronic submission requirement for BPDRs, and blood transfusion and
collection fatality reports in the near future and would like to
receive industry comment on this possibility.

C. Waivers

    Although this proposed rule would require that all postmarketing
safety reports be submitted to FDA in electronic format, we are
proposing in Sec. Sec.  310.305(e)(2), 314.80(g)(2), and 600.80(g)(2)
to grant a temporary waiver from the electronic format requirement for
``good cause'' shown. Procedural details for submitting waiver
requests, such as where to send the request and any supporting
documentation, would be announced in guidance. When a temporary waiver
has been granted, a

paper copy of the safety reports would be required to be submitted in a
form that FDA can process, review, and archive.\29\ FDA anticipates
that temporary waivers of the requirement to submit postmarketing
safety reports to the agency in electronic format will only be needed
in rare circumstances. Companies experiencing technical difficulties
with their ESG interface could, as a backup, submit reports on physical
media or using the Web-based form during short-term, temporary outage.
Moreover, for companies that rely on the Web-based form, submissions
could be made from any computer with an Internet connection, providing
ample alternatives should the company experience a longer term
interruption of Internet service at its offices. Accordingly, we seek
comments on what circumstances would constitute ``good cause'' for
granting waivers.
---------------------------------------------------------------------------

    \29\ FDA's ability to process, review, and archive postmarketing
safety reports submitted to the agency in a paper format is
described in FDA's draft guidance for industry on ``Postmarketing
Safety Reporting for Human Drug and Biological Products Including
Vaccines'' available on the Internet at http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/default.htm under
``Procedural'' or at http://www.fda.gov/cber/guidelines.htm.
---------------------------------------------------------------------------

D. Individual Case Safety Report (ICSR)--Definition and Required
Information

    The term ICSR is used to describe the information contained on
either an initial or followup report of an individual adverse drug
experience, currently reported on an FDA Form
    3500A, CIOMS I form, VAERS form, or in electronic format. Given
that this proposed rule would require that all safety reports be
submitted in electronic format, we believe describing the safety
reporting vehicle generically, rather than by reference to the
associated paper form, is appropriate. Accordingly, we are proposing in
Sec. Sec.  310.305(b), 314.80(a), and 600.80(a) (with minor
modifications) to define an ICSR as a description of an adverse drug
experience related to an individual patient or subject. Because the
items of information which should be reported in an ICSR are currently
specified on the paper reporting forms that will no longer be used, we
are also proposing to add a list of the reportable elements in the
regulations. Accordingly, proposed Sec. Sec.  310.305(d), 314.80(f),
and 600.80(f) would provide a detailed list of specific types of
information in five broad categories that are to be reported on the
ICSR. The proposed categories, and examples of some of the types of
information in each category, are as follows:
     Patient information (e.g., patient identification code,
age, gender);
     Information about the adverse drug experience (e.g., date
and description of the adverse drug experience);
     Information about the drug (e.g., drug name, dose,
indication, National Drug Code (NDC) number);
     Information identifying the initial reporter (e.g., name
and contact information); and
     Information about the drug's applicant or manufacturer
(e.g., name and contact information).
    Other than minor wording differences, this proposed list of
information to be reported is the same as that currently reflected on
the FDA Form 3500A for postmarketing reporting for drugs and biological
products. Codification of the ICSR reporting requirements is not
intended to change the existing obligation of manufacturers, packers,
or distributors to exercise due diligence for purposes of completing
all of the applicable elements of an ICSR. The obligation to provide
all applicable information described in proposed Sec. Sec.  310.305(d),
314.80(f), or 600.80(f) would be the same as the current obligation to
complete the FDA Form 3500A.\30\
---------------------------------------------------------------------------

    \30\ For FDA's current thinking on ``due diligence,'' see the
guidance described in footnote 29 of this document.
---------------------------------------------------------------------------

E. Removal of Paper Format Provisions

    FDA believes that it is no longer necessary to describe procedures
for paper format submissions in its regulations because the agency
anticipates that a paper format will be used on a very limited basis,
if at all. Accordingly, FDA is proposing to remove from its regulations
provisions describing the details for submission of safety reports in
paper format, such as the number of required paper copies or specific
markings or notations required on the paper forms. We are proposing to
delete in Sec. Sec.  310.305(d), 314.80(f) and 600.80(f) the provisions
specifically describing paper submissions and replace them with a new
paragraph (proposed Sec. Sec.  310.305(e)(1), 314.80(g)(1) and
600.80(g)(1)), which states that ICSRs and any attachments must be
submitted to FDA in an electronic format that we can process, review,
and archive. In addition, we are proposing to revise current
regulations to remove or modify the following references or provisions
that are specific to paper formats:
     References to the number of paper copies required for
safety report submissions (Sec. Sec.  310.305(c) , 314.80(c), and
600.80(c));
     The requirement to mark paper reports to identify their
contents as ``15-day Alert report'' or ``15-day Alert report-
followup,'' (Sec. Sec.  310.305(c)(4), 314.80(c)(1)(iv),
600.80(c)(1)(iv));
     The requirement to use FDA Form 3500A, CIOMS I form, or
VAERS form or to determine an appropriate alternative format for
voluntary submission in electronic format (Sec. Sec.  310.305(d)(1) and
(3); 314.80(f)(1) and (3), and 600.80(f)(1) and (3));
     The reference to FDA Form 3500A or other paper forms
designated for adverse drug experience reporting by FDA for ICSRs that
are submitted as part of periodic reporting requirements (Sec. Sec.
314.80(c)(2)(ii)(b) and 600.80(c)(2)(ii)(B)); and
      The requirement for identifying reports of adverse drug
experiences that occur in postmarketing studies by separating and
marking them (Sec. Sec.  314.80(e)(2), and 600.80(e)(2)).
    As discussed previously in this document, in the future, procedural
and formatting details, if applicable to electronic submissions, will
be included in guidance, rather than in regulations.

F. Miscellaneous Changes

    The proposal would amend Sec. Sec.  310.305, 314.80, 314.98, and
600.80 by replacing the word ``shall'' with the word ``must'' except in
the first sentence of Sec. Sec.  314.80(c)(1)(iii) and
600.80(c)(1)(iii), from which the word ``shall'' would be removed for
editorial reasons. FDA is also proposing to revise in Sec.
314.80(c)(2) the paragraph designations that are currently not in
correct format. FDA anticipates that these minor changes will clarify
the regulations and make them easier to read. FDA is also proposing to
change the term ``licensed manufacturer'' to ``applicant'' in
Sec. Sec.  600.80, 600.81 and 600.90.
    Current Sec. Sec.  310.305(c), 314.80(c), 314.98(b), and 600.80(c)
provide mailing addresses for the submission of postmarketing safety
reports. FDA is proposing to remove these mailing addresses from its
regulations because this information is provided in guidance and it is
easier to update guidances when an address changes.
    Under current Sec.  310.305(c)(1)(i), each report must be
accompanied by a copy of the labeling. We are proposing to revise this
section to require the submission of the current content of labeling in
electronic format unless it is already on file with FDA.
    Currently, ICSRs for all adverse drug experiences other than those
reported as 15-day Alert or followup reports (i.e., reports of serious,
expected or nonserious adverse drug experiences)

are submitted as a batch as part of the postmarketing periodic safety
report for the period during which the events occurred. Although the
ICSRs may be generated at any time during the reporting period, they
are retained by the applicant during the reporting period and submitted
to FDA all at once, along with the other (descriptive) portions of the
periodic report. FDA is including language in proposed Sec. Sec.
314.80(c)(2)(B) and 600.80(c)(2)(B) to give applicants the option of
submitting these ICSRs at any time during the reporting period, rather
than waiting to submit them in a single batch with the descriptive
information. As with current submission procedures, all ICSRs of
serious, expected or nonserious adverse drug experiences occurring
during the reporting period would still be due to the agency by the
time the descriptive information is submitted for that period, but the
proposed change would permit them to be filed anytime during the
reporting period, rather than all at once with the narrative portion of
the periodic report. We understand that many applicants would prefer
this added flexibility of submitting the ICSRs on an ongoing basis.
    Current postmarketing safety reporting regulations at Sec. Sec.
310.305(e), 314.80(h), and 600.80(h) state that persons subject to
these requirements should not include the names and addresses of
individual patients in reports and, instead, should assign a unique
code number to each report, preferably not more than eight characters
in length. Proposed Sec. Sec.  310.305(f), 314.80(i), and 600.80(i)
would remove the eight character limit from the provision and add that
the preferred methodology for determining the identification code would
be set forth in technical specifications referenced in FDA guidance
documents. Specific details of this type are most appropriate in the
technical specifications referenced in FDA guidance documents, which
can be more easily revised as technological requirements change. In
addition, these provisions require that the entity submitting the
report to FDA include in the ICSR the name of the reporter from whom
the information was received. We are proposing to add an exception so
that the name of the reporter need not be disclosed in situations where
the reporter is also the patient.
    Current Sec. Sec.  310.305(c)(1), 314.80(c)(1)(i), and
600.80(c)(1)(i) require that 15-day Alert reports be submitted ``as
soon as possible but in no case later than 15 calendar days of initial
receipt of the information'' by the person. We propose to revise this
language to state ``as soon as possible, but no later than 15 calendar
days from initial receipt of the information.'' FDA does not intend
this proposed change to have any substantive effect. It is being made
solely to simplify the regulatory language and improve its readability.

G. Proposed Implementation Timeframe

    FDA proposes that any final rule that may issue based on the
proposal become effective 1 year after its date of publication in the
Federal Register. FDA believes that 1 year is sufficient because many
companies are currently submitting their postmarketing safety reports
electronically to the agency using ICH standards and more than 1 year
is not needed for companies that would choose to set up this system for
their submissions. For companies that choose to use the Web-based
system, the transition from paper submissions to electronic submissions
will be as simple as filling out forms on the Internet and would,
therefore, not necessitate more than 1 year to implement. (See section
II.D.1.c of this document for discussion.)

IV. Legal Authority

    FDA's legal authority to amend its regulations governing the
submission of postmarketing safety reports for human drugs and
biological products derives from sections 201, 301, 501, 502, 503, 505,
505A, 506, 506A, 506B, 506C, 510, 701, 704, 705, 760, and 801 of the
act (21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356, 356a, 356b,
356c, 360, 371, 374, 375, 379aa, and 381); and the Public Health
Service Act (42 U.S.C. 241, 262, and 264).

V. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

VI. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is not a significant regulatory action as defined by
the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the average small entity submits very few
safety reports and the agency's proposed Web-based method to submit
reports electronically would require little additional cost per report,
the agency does not believe that this proposed rule would have a
significant economic impact on a substantial number of small entities.
FDA requests comment on this issue.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $133 million, using the most current (2008) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.
    The major benefit of this proposed rule would be to public health
and the agency in the form of quicker access to postmarketing safety
information and an annual savings of about $2.4 million, including a
savings in the cost of paper. Total one-time costs to industry would be
between $4.5 million to $5.6 million; most of these costs would be for
changing standard operating procedures (SOPs), setting up systems for
submissions, and acquiring an electronic certificate. Industry would
also incur annual costs of between $133,320 to $139,380 for Internet
upgrades and to maintain electronic certificates.
    The proposed rule would require the submission of all postmarketing
safety reports, including periodic reports, to FDA in an electronic
format. It would affect all persons required to submit postmarketing
safety reports under Sec. Sec.  310.305, 314.80, 314.98, 600.80, and
600.81. As currently proposed, this rule would not change the content
of the postmarketing safety reports or the frequency of the reporting
requirements. The proposal is part of the agency's initiative to adopt
electronic technologies to improve the quality of our operations and
increase our efficiency.

    A regulation is necessary because the majority of the benefits from
increased effectiveness of FDA use of adverse drug experience reports
will accrue to the agency and to public health, while the costs are
borne by industry. Many of the firms lack the private incentive to
divert resources to develop electronic submission capabilities on their
own. In other words, for many firms the present value of the cost
savings from eliminating paper reports is less than the cost of
switching to electronic reports. Without this regulation, the agency
would need to maintain adequate resources to convert paper reports to
electronic records until all companies adopt the electronic submission
format, possibly years in the future. Although some part of this
proposed rule would merely shift costs of adopting the electronic
format from FDA to industry, the additional social benefit arises from
the increased speed and effectiveness of FDA analyses and action based
on adverse drug experience reports. The need for the regulation stems
from the benefits to the public health from more rapid identification
and action on unanticipated adverse drug experiences.
    FDA currently accepts postmarketing safety reports submitted
electronically using ICH standards (i.e., ICH M2 transmission standards
and ICH E2BM data elements) (see section II.D.1.b of this document).
Both the EU and Japan have mandated electronic submissions for
postmarketing safety reports using these standards. The proposed rule
would make the FDA's system compatible with the systems used in Japan
and the EU. The proposed rule may also increase the use of
international data and international comparisons, which could
contribute to more rapid identification and action on serious and
unexpected adverse drug experiences.

A. Benefits

    The proposal would reduce FDA's current costs associated with
processing postmarketing safety reports that are received via paper
format. By receiving these reports electronically, FDA would be able to
access the safety information more quickly and also reduce data entry
errors that could occur during entry of the information from the paper
reports into our electronic system. The major benefits of this proposed
rule would be to the agency and public health in terms of quicker
access to postmarketing safety information, which in turn would lead to
faster identification of safety problems. The proposed rule would also
reduce the agency's costs for converting paper records in a variety of
formats into electronic form. Resources that are now used to manually
enter the reports into FDA's electronic database could be redirected to
monitoring drug safety or other agency initiatives.
    Currently, the agency receives more than 445,000 postmarketing
ICSRs per year. In fiscal year 2006, approximately 60 percent of ICSRs
(15-day Alert and periodic) were submitted in paper form. At this time,
it takes from 3 to 14 days before a submitted paper record of a 15-day
Alert report is available for analysis in the AERS database. Periodic
ICSRs submitted on paper may not be entered into AERS for up to 60
days. With a standardized electronic format, records would become
available for analysis in AERS as soon as they were processed by FDA
(within 2 days of receipt by the agency).
    The agency currently spends about $5.4 million annually on
conversion of paper ICSRs to an electronic format, which includes data
entry and quality control.\31\ The proposal would result in reduced
costs associated with controlling and ensuring the quality of the data.
Assuming that the number of reports remains fairly constant over time,
we estimate that we would save about $2.4 million annually in
contracting costs by not having to convert paper copies to an
electronic format.
---------------------------------------------------------------------------

    \31\ Cost to convert paper reports to electronic format from FDA
AERS data entry contract.
---------------------------------------------------------------------------

    The larger public health benefits--more timely identification of
drug safety problems with the potential to reduce subsequent adverse
drug experiences--cannot be realized fully until a comprehensive
surveillance system and international harmonization of reporting
requirements are in place (e.g., implementation of the ICH standards
discussed in the Safety Reporting Proposed Rule). Obtaining
postmarketing safety reports in an electronic format is an important
and necessary step toward attaining the larger public health benefits.

B. Costs

    FDA estimates that there are approximately 2,020 firms affected by
this rule. Table 1 lists the number of firms affected by type of
product marketed. To comply with the proposed rule, firms would incur
both one-time and annually recurring costs. One-time costs include
modifying SOPs, developing electronic submission capabilities, and
training employees on the new procedures. Annually recurring costs
would include the cost to maintain an electronic certificate and high-
speed Internet access. There would be no change in the actual time
required to research and prepare the report, nor would there be any
additional reporting requirements as a result of this proposed rule.
    As discussed earlier in this preamble, firms marketing
nonprescription drug products without an approved application are now
subject to safety reporting requirements as a result of Public Law 109-
462 (see section II.A.1.d of this document). Although this rule does
not propose to require use of an electronic format for submission of
these reports, because we are considering such a requirement for the
final rule, this analysis includes an estimate of the incremental cost
for firms to comply with the submission of these safety reports in an
electronic format. While the mandatory reporting requirements are new,
analyzing product complaints, including reports of drug induced adverse
drug experiences, is a requirement of the Current Good Manufacturing
Practice regulations (21 CFR 211.198).
1. One-time costs
    a. Rewriting standard operating procedures and training personnel.
Almost all companies would have to make some changes to their SOPs to
reflect the requirements for electronic submission versus mailing the
reports to the agency. Most companies that submit postmarketing safety
reports to FDA are small and submit few safety reports to the agency;
we estimate that it would require about 10 hours to change their SOPs
and to train the appropriate employees. Companies with proprietary
computer systems used to generate and store safety reports would
require considerably more time to modify their SOPs and train the
appropriate personnel. We estimate that these firms would require about
50 hours for this task.
    We estimate that about 1,520 firms would require 10 hours and about
100 firms would require 50 hours to modify SOPs and train the
appropriate personnel. (The firms primarily marketing nonprescription
drug products without an approved application are not included in this
estimate.) Assuming an average wage rate including benefits of $68 per
hour, the total one-time incremental cost for this proposed requirement
would be about $1.4 million [(1,520 x 10 hours x $68) + (100 x 50 hours
x $68)] (see table 1 of this document).\32\
---------------------------------------------------------------------------

    \32\ Wage derived from 2007 Bureau of Labor Statistics
Occupation Employment Statistics Survey, standard occupation code
11-3042, training manager for pharmaceutical medicine and
manufacturing--mean wage rate $48.73 + 40 percent for nonwage
benefits and rounded to $68, at www.bls.gov.

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

    Firms producing primarily nonprescription drug products without an
approved application will have to establish SOPs for submitting ICSRs.
We estimate that it takes between 24 and 40 hours to write a new SOP
and another 5 to 10 hours to train the appropriate personnel, depending
on the size of the firm.\33\ Assuming an average wage cost of $68 per
hour, and the mid-point of the range of hours the cost would be about
$1.1 million (40 hours x $68 x 400 firms).
---------------------------------------------------------------------------

    \33\ Eastern Research Group, ``Economic Threshold and Regulatory
Flexibility Assessment of Proposed Changes to the Current Good
Manufacturing Practice Regulations for Manufacturing, Processing,
Packing, or Holding Drugs,'' submitted to the Office of Planning and
Evaluation, March 1995.
---------------------------------------------------------------------------

    b. Setting up system for submission. ICSRs would be submitted
through FDA's electronic submission gateway (ESG) using one of two
methods: One at a time using a Web-based form or by direct transmission
through an ICH compatible system. Attachments to the ICSRs, the
descriptive information portion of periodic reports and distribution
reports would be submitted as PDF files through the ESG. We assumed
that because most firms are small and submit few ICSRs, they would use
the Web-based form. To comply using this submission method, firms would
need high speed Internet connections and would have to download and
install up to two free software programs, validate the installation,
and train the appropriate personnel on the new procedures. Firms that
have dedicated IT staff would be able to install and validate the
installation themselves. Smaller firms would probably choose to hire an
outside contractor for the installation and validation. We do not have
data on the amount of time required to install and validate the
installation of the software or the percentage of firms that might need
to contract out the installation. For this analysis, we assumed it
would take 8 to 16 hours to install and validate the installation of
the Java Runtime Edition software and the Java security policy files
for the company's Internet browser.\34\ This estimate also includes the
time required to notify FDA and run a test submission through the FDA
ESG and to train the appropriate staff. Based on these assumptions and
using the $68 per hour wage the cost for this requirement would range
from $1.0 million to $2.1 million (8 hours x $68 wage x 1,920 firms and
16 hours x $68 wage x 1,920 firms).
---------------------------------------------------------------------------

    \34\ See http://www.fda.gov/esg/default.htm#tutorials and http:/
/www.fda.gov/esg/account.htm.
---------------------------------------------------------------------------

    Firms that submit a large number of reports each year may chose to
use the ICH compatible method. This method allows for the submission of
multiple reports at faster transmission rates. We do not know at what
threshold of reporting it becomes cost effective for a firm to submit
reports using this method. Currently just over 40 firms voluntarily
submit ICSRs using this method and they account for about one-half of
all 15-day Alert reports submitted each year. We assume that only firms
that have existing infrastructure to support the ICH method of
transmission would choose this method to submit reports. At the time of
a final rule we estimate that about 50 firms would be voluntarily using
this method of submission and about 100 additional firms would comply
with the rule by adopting this method of reporting for an estimated
cost of $0.3 million (50 hours x $68 x 150 firms).
    c. Electronic certificate. All firms would need an electronic
certificate to submit any document to the FDA ESG. The electronic
certificate identifies the sender and serves as an electronic
signature. Firms that have not submitted any electronic documents to
the agency would incur a one-time cost to acquire the certificate and
recurring costs to keep the certificate active as a result of this
proposed rule. The certificates cost about $20 and are good for 1 year.
We assume that the search and transactions costs involved in the
initial acquisition of the certificate double the cost of the
certificate to $40 for the first year, half of which would be set-up
costs. We also believe that should this rule become final many firms
will already have electronic certificates because they are required for
electronic submission of other regulatory documents, such as product
applications and supplements. If 60 to 70 percent of the firms needed
to acquire an electronic certificate to comply with the proposed
requirement, the cost would be between $48,480 and $56,560 ($40 x 1,212
firms and $40 x 1,414 firms, respectively).
    In addition to the costs we have estimated, some firms affected by
this proposed rule may have to hire outside expertise to install and
validate the software installation to comply with the proposed
requirements.
    d. Creation of PDF files. Some companies still maintain safety
information as paper records. Companies that store their submissions in
paper format rather than electronically may also incur costs to acquire
the ability to convert ICSR attachments, the descriptive information
portion of periodic reports, and distribution reports to an electronic
format that the agency can process, review, and archive. Currently,
this is the PDF format. We assume all firms would have the software and
training necessary to convert existing electronic files to a PDF
format.
    We lack sufficient data to estimate with any certainty the costs to
convert paper documents to electronic files that can be transmitted
through our ESG. We do not know how many companies maintain paper
versus electronic records. We also do not know how many have optical
scanning capabilities that would allow them to convert the paper
records to electronic PDF files.
    Because optical scanners are relatively inexpensive and easy to
use, they are commonplace in businesses today. We believe that all of
the large firms in the industry currently have such equipment and would
incur little or no additional incremental costs for this capability.
Most large firms currently store much of their information
electronically now, and they should require no more than 30 minutes to
convert ICSR attachments to PDF files and proof them, which would be
offset by the time they currently use for photocopying, collating, and
mailing files. For documents the applicant has in paper format, the
time required to scan a document would also be offset by no longer
having to photocopy, collate, and mail the submission to us.
    Companies that maintain their records in a paper format may have to
purchase an optical scanner and the appropriate optical character
recognition (OCR) software to comply with this requirement, or they
could pay a service provider, such as a copy center, to transform the
documents into an electronic PDF file. A suitable scanner with OCR
software should not cost more than $400. FDA assumes that initial setup
and training to use the equipment should require no more than 4 hours.
At the wage plus benefits rate of $68 per hour, the one-time cost for
setup and training would be about $272 (4 hours x $68). If one-half of
the companies affected needed to purchase a scanner and train employees
to use it, the total one-time costs would be $0.7 million (($400 +
$272) x 1,010) (see table 1 of this document).
    To have a service provider convert a black and white paper document
to a PDF file would cost about $10 per page for the first page and
about $2 per page thereafter. If an applicant wanted the documents
saved to a disk, it would cost an additional $20 per transaction.

    Safety report submissions differ greatly in the number of
attachments and number of pages submitted depending on the nature of
the adverse drug experience and the drug involved. We do not have an
estimate of the number of pages of attachments in an average report.
However, if an applicant used a service provider to convert 20 pages of
material and had it saved to a disk, it would cost about $70 ($10 first
page + ($2 x 19 pages) + $20 to save to disk).
    The total one-time incremental costs of this proposed rule would be
between $4.5 million and $5.6 million. About $1.4 million to $1.7
million of this total would be incurred by the firms that primarily
market nonprescription drug products without an approved application.
(table 1 of this document).
2. Annual costs
    The annual costs of this proposed rule would include the costs of
maintaining electronic certificates and the increased cost for some
firms to obtain high-speed Internet access.
    a. Maintaining the electronic certificate. Firms would have an
annual cost to renew the electronic certificate that identifies the
sender. In addition to having to renew the certificate on a regular
basis, firms that seldom submit reports would also have to ensure they
are capable of transmitting data to the agency. To add these additional
costs to the cost of the certificate itself, we assume that firms incur
an additional annually recurring cost equal to one-half the price of
the certificate ($10), for a total annually recurring cost of $30.
Assuming that 60 to 70 percent of the firms would not voluntarily
submit any required documents electronically without a regulation, the
annual cost to maintain certificates would range from $36,360 and
$42,420 ($30 x 1,212 firms or $30 x 1,414 firms).
    b. High-Speed Internet access. Firms will need high-speed Internet
access to use either of the submission methods. A 2004 study of small
businesses sponsored by the Small Business Administration found that
essentially all small firms in the United States had Internet access
and about 50 percent had high-speed Internet access.\35\ The average
cost of high-speed access was about $40 per month more than dial-up
access. Because of the nature of the drug industry and because the
average cost of Internet access has been going down over time, we
estimate that by the time this proposed rule would be made final, about
90 percent of firms would have high speed access. The average annual
recurring increase in cost for high speed Internet access for the
remaining 10 percent of firms would be $96,960 ($40 x 12 months x 202
firms).
---------------------------------------------------------------------------

    \35\ Pociask, Steve, ``A Survey of Small Businesses'
Telecommunications Use and Spending,'' Small Business Administration
Office of Advocacy contract number SBA-HQ-02-M-0493, March 2004.
---------------------------------------------------------------------------

    Table 2 shows the annual costs of the proposed rule. As with the
one-time costs, only firms not already making electronic submission of
any kind to the agency when this proposed rule becomes final would
incur these costs.

C. Summary of Benefits and Costs

    The principal benefit of this proposed rule would be the public
health benefits associated with more rapid processing and analysis of
the almost 300,000 ICSRs currently submitted on paper. In addition,
requiring electronic submission would reduce FDA annual operating costs
by $2.4 million.
    The total one-time cost for modifying SOPs and establishing
electronic submission capabilities is estimated to range from $4.5
million to $5.6 million. Annually recurring costs totaled $133,320 to
$139,380 and included maintenance of electronic submission
capabilities, including renewing the electronic certificate, and for
some firms the incremental cost to maintain high-speed Internet access.
The total annualized cost of the proposed rule, assuming a 7-percent
discount rate over 10 years, would be from $0.8 million to $0.9 million
($0.7 million to $0.8 million at a 3-percent discount rate). We request
comment on the accuracy and completeness of the assumptions used to
estimate the costs of this proposed rule, including our choice of a 10
year time horizon.

D. Alternatives Considered

    During the development of this proposed rule, we considered a
number of alternative approaches. The first was to allow persons to
voluntarily submit reports electronically. This option is currently
available and our experience has shown that a number of companies would
resist changing their procedures for a long time. As a result, we would
not attain the benefits of standardized formats and quicker access to
adverse drug experience data with voluntary electronic submissions.
    Another alternative was to allow small entities a longer period of
time to comply with the electronic submission requirements. This
alternative would have allowed small entities to delay the expense of
compliance. This alternative would delay our receiving the full
benefits of quicker access to these reports. Compliance costs for small
entities are estimated to be low, less than $2,260 in one-time costs
(sum of cost for equipment, training, and changing SOPs), which should
not impose an economic hardship on the small entities.
    We also considered requiring electronic submissions but not
specifying a format. This alternative would reduce the costs to firms
associated with paper. Because receiving reports in many different
formats would continue to require the agency to convert the reports
into a standard format for analysis, this alternative would delay the
full public health benefits of quicker FDA access to these reports.

E. Small Business Impact

    The Small Business Administration defines an entity in the
pharmaceutical industry as small if it has fewer than 750 employees and
a biologic entity as small if it has fewer than 500 employees. Based on
this definition about 90 percent of the drug and biologic entities are
small. The impact on each entity will vary depending on their
electronic submission capabilities when the rule is made final. Much of
the incremental cost and all of the recurring costs of this proposed
rule are for acquiring and maintaining electronic submission capability
($1,236 to $1,780 in one-time costs and up to $510 in annually
recurring costs per small entity). Only firms that have not made any
electronic submissions to the agency when this rule becomes final would
incur those costs. The writing of SOPs and employee training are the
only costs that are specific to this rule (a one-time cost of about
$680 per small entity).
    Because the estimated incremental costs per entity are low, between
$1,916 and $2,460 in one-time incremental costs and up to $510 in
annually recurring costs, and the majority of those costs would be
incurred for any electronic submission across the agency, this proposed
rule would probably not have a significant economic impact on a
substantial number of small entities. However, because we lack data to
fully characterize the small entities and the average submittal, we do
not certify that there will be no significant impact at this time. We
request comment on the tentative conclusion of no significant impact.

                                                        Table 1.--One-Time Costs by Firm Type\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                Establishing  e-submission capability           Acquiring  e-                             Total
                                  Total   ------------------------------------------------     certificate\1\                  -------------------------
         Type of Firm           number of   Modifying                              ICH    ------------------------  PDF files
                                  firms       SOPs         Low        High       Method        Low        High                      low          high
--------------------------------------------------------------------------------------------------------------------------------------------------------
Drug and biologic products            600    $680,000    $272,000    $544,000    $340,000      $7,200      $8,400     $201,600   $1,500,800   $1,774,000
 subject to parts 310, 314,
 and 600
--------------------------------------------------------------------------------------------------------------------------------------------------------
Nonprescription drug products         400   1,088,000     217,000     435,200  ..........       4,800       5,600      134,400    1,444,800    1,663,200
 marketed without an approved
 application
--------------------------------------------------------------------------------------------------------------------------------------------------------
Medical Gas                         1,020     693,300     554,880   1,109,760  ..........      12,240      14,280      342,720    1,603,440    2,160,360
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                               2,020  $2,461,600  $1,044,480  $2,088,960    $340,000     $24,240     $28,280     $678,720   $4,549,040   $5,597,560
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized at 3% over 10       ..........  ..........  ..........  ..........  ..........  ..........  ..........  ...........     $553,286     $656,205
 years
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized at 7% over 10       ..........  ..........  ..........  ..........  ..........  ..........  ..........  ...........      $647681     $796,967
 years
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\This refers to the $20 one-time cost involved in acquiring the certificate, the actual cost of the certificate is captured in the annual recurring
  costs (table 2 of this document).

                                        Table 2.--Annual Recurring Costs
----------------------------------------------------------------------------------------------------------------
                          Electronic Certificate                                            Total
   Type of Firm   --------------------------------------  Internet access  -------------------------------------
                          Low                High                                  Low                High
----------------------------------------------------------------------------------------------------------------
Drug and biologic            $10,800            $12,600            $28,800            $39,600            $41,400
 products subject
 to parts 310,
 314, and 600
----------------------------------------------------------------------------------------------------------------
Nonprescription                7,200              8,400             19,200             26,400             27,600
 drug products
 marketed without
 an approved
 application
----------------------------------------------------------------------------------------------------------------
Medical Gas                   18,360             21,420             48,960             67,320             70,380
----------------------------------------------------------------------------------------------------------------
Total                        $36,360            $42,420            $96,960           $133,320           $139,380
----------------------------------------------------------------------------------------------------------------

VII. Paperwork Reduction Act of 1995

    This proposed rule contains collections of information that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 3520). ``Collection
of information'' includes any request or requirement that persons
obtain, maintain, retain, or report information to the agency, or
disclose information to a third party or to the public (44 U.S.C.
3502(3) and 5 CFR 1320.3(c)). The title, description, and respondent
description of the information collection are shown under this section
with an estimate of the annual reporting burden. Included in the
estimate is the time for reviewing instructions, searching existing
data sources, gathering and maintaining the data needed, and completing
and reviewing the collection of information.
    We invite comments on these topics: (1) Whether the collection of
information is necessary for proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
    Title: Postmarketing Safety Reports for Human Drug and Biological
Products: Electronic Submission Requirements.
    Description: The proposed rule would amend FDA's postmarketing
safety reporting regulations for human drug and biological products,
under parts 310, 314 and 600, to require that persons subject to
mandatory reporting requirements submit safety reports in an electronic
format that FDA can process, review, and archive. Under Sec. Sec.
310.305, 314.80, 314.98 and 600.80, manufacturers, packers, and
distributors, and applicants with approved NDAs, ANDAs and BLAs and
those that market prescription drugs for human use without an approved
application must currently submit postmarketing safety reports to the
agency. Under Sec.  600.81, applicants with approved BLAs must
currently submit biological lot distribution reports to the agency. In
this rule, FDA is proposing to require that these postmarketing reports
be submitted to the agency in an electronic format that FDA can
process, review and archive. We also propose to add language to these
sections which states that FDA will periodically issue guidance on how
to provide the electronic submissions (e.g., method of transmission,
media, file formats, preparation and organization of files). This rule
does not change the content of these postmarketing reports. It only
proposes to require that they be submitted in an electronic form. Under
Sec. Sec.  310.305(e)(2), 314.80(g)(2), 600.80(g)(2), and 600.81(b)(2),
we are also proposing to permit manufacturers, packers, and
distributors, and applicants with approved NDAs, ANDAs and BLAs and
those that market prescription drugs for human use without an approved
application to request a waiver from the electronic format requirement.
    We currently have OMB approval for submission of postmarketing
safety reports to FDA under parts 310, 314,

and 600. The information collection for part 310 and part 314 is
approved under OMB Control Numbers 0910-0291 (Form 3500A) and 0910-
0230. The information collection for part 600 is approved under OMB
Control Numbers 0910-0291 (Form 3500A) and 0910-0308. We do not expect
that the burdens currently estimated, under parts 310, 314 and 600, for
submission of postmarketing safety reports to FDA for human drugs and
biological products would change as a result of this proposed rule.
This is because: (1) Current burden estimates associated with these
regulatory requirements have taken into account voluntary submission of
these reports in an electronic format and those applicants,
manufacturers, packers, and distributors that already submit these
reports in an electronic format would have no new reporting burdens,
and (2) new burdens for establishing the means for submitting
postmarketing safety reports in electronic form to comply with this
proposed rule, including obtaining an electronic certificate, revising
SOPs, and familiarity with the system, would be negated by the savings
in burden from not having to print out the report and mail it to FDA.
These assumptions also apply to applicants submitting biological lot
distribution reports under proposed Sec.  600.81. We invite comment on
the number of respondents not currently submitting safety reports in
electronic format who would need to convert from paper submission. We
also invite comment on the reduction in burden associated with not
printing out reports and mailing them to FDA and whether this burden
reduction is offset by the cost associated with obtaining an electronic
certificate, revising SOPs, and familiarizing firms with the system.
    Manufacturers, packers, or distributors whose name appears on the
label of nonprescription human drug products marketed without an
approved application are now required to submit reports of serious
adverse events to FDA (see section II.A.1.d of this document). Even
though we are not proposing to require that these reports be submitted
to FDA in an electronic form at this time, we are considering including
such a requirement in the final rule. OMB has recently approved the
burden associated with these submissions under OMB Control Number 0910-
0636.
    In table 3 of this document, we have estimated the burdens
associated with submission of waivers, under proposed Sec. Sec.
310.305(e)(2), 314.80(g)(2), 600.80(g)(2), 600.81(b)(2) and 21 U.S.C.
379aa((b) and (c)). We expect very few waiver requests (see section
III.C of this document). We estimate that approximately one
manufacturer would request a waiver annually under Sec. Sec.
310.305(e)(2), 600.81(b)(2), and 21 U.S.C. 379aa((b) and (c)), and five
manufacturers would request a waiver annually under Sec. Sec.
314.80(g)(2) and 600.80(g)(2). We estimate that each waiver request
would take approximately 1 hour to prepare and submit to us.
    Description of Respondents: Manufacturers, packers, and
distributors, and applicants with approved NDAs, ANDAs and BLAs and
those that market prescription drugs for human use without an approved
application.
    Burden Estimate: Table 3 of this document provides an estimate of
the annual reporting burden for submitting requests under the proposed
waiver requirement in this rule.

A. Reporting Cost

                         Table 3.--Total Estimated Annual Burden For This Proposed Rule
----------------------------------------------------------------------------------------------------------------
                                          Number of
 21 CFR Sections       Number of        Responses Per       Total Annual        Hours per         Total Hours
                      Respondents         Respondent         Responses           Response
----------------------------------------------------------------------------------------------------------------
Waivers            .................  .................  .................  .................  .................
----------------------------------------------------------------------------------------------------------------
310.305(e)(2)                      1                  1                  1                  1                  1
----------------------------------------------------------------------------------------------------------------
314.80(g)(2)                       5                  1                  5                  1                  5
----------------------------------------------------------------------------------------------------------------
600.80(g)(2)                       5                  1                  5                  1                  5
----------------------------------------------------------------------------------------------------------------
600.81(b)(2)                       1                  1                  1                  1                  1
----------------------------------------------------------------------------------------------------------------
21 U.S.C.                          1                  1                  1                  1                  1
 379aa((b) and
 (c))
----------------------------------------------------------------------------------------------------------------
Total Reporting Burden                                                                                13
----------------------------------------------------------------------------------------------------------------

    Based on the average hourly wage as calculated in section VI
(Analysis of Impacts) of the proposed rule ($68), the cost to
respondents would be $884 (13 X $68).
    Tables 4 through 7 of this document provide an estimate of the
annual reporting burden currently covered under existing OMB Control
Numbers 0910-0291, 0910-0230, 0910-0308, and 0910-0636. As explained
previously, we believe that any burden increases associated with
electronic reporting are offset by burden decreases associated with not
printing out reports and mailing them to FDA. Therefore, we believe
that the burden estimates for these information collections will not
change.

                                     Table 4.--OMB Control Number 0910-0291
----------------------------------------------------------------------------------------------------------------
                                          Number of
 21 CFR Sections       Number of        Responses Per       Total Annual        Hours per         Total Hours
                      Respondents         Respondent         Responses           Response
----------------------------------------------------------------------------------------------------------------
Form 3500A (Sec.                 600                765            459,102                1.1           505, 012
 Sec.   310.305,
 314.80, 314.98,
 & 600.80)
----------------------------------------------------------------------------------------------------------------

    Based on the average hourly wage as calculated in section VI
(Analysis of Impacts) of the proposed rule ($68), the cost to
respondents would be $34,340,816 (505,012 x $68).

                                     Table 5.--OMB Control Number 0910-0230
----------------------------------------------------------------------------------------------------------------
                                          Number of
 21 CFR Sections       Number of        Responses Per       Total Annual        Hours per         Total Hours
                      Respondents         Respondent         Responses           Response
----------------------------------------------------------------------------------------------------------------
310.305(c)(5)                      1                  1                  1                  1                  1
----------------------------------------------------------------------------------------------------------------
314.80(c)(2)                     642              17.88             11,478                 60            688,680
----------------------------------------------------------------------------------------------------------------
Total                                                                                688,681
----------------------------------------------------------------------------------------------------------------

    Based on the average hourly wage as calculated in section VI
(Analysis of Impacts) of the proposed rule ($68), the cost to
respondents would be $46,830,308 (688,681 x $68).

                                     Table 6.--OMB Control Number 0910-0308
----------------------------------------------------------------------------------------------------------------
                                          Number of
 21 CFR Sections       Number of        Responses Per       Total Annual        Hours per         Total Hours
                      Respondents         Respondent         Responses           Response
----------------------------------------------------------------------------------------------------------------
600.80(c)(1) &                    88             270.85             23,835                  1             23,835
 600.80(e)
----------------------------------------------------------------------------------------------------------------
600.80(c)(2)                      88             248.55             21,872                 28            612,416
----------------------------------------------------------------------------------------------------------------
600.81                            88               2.03                179                  1                179
----------------------------------------------------------------------------------------------------------------
Total                                                                                636,430
----------------------------------------------------------------------------------------------------------------

    Based on the average hourly wage as calculated in section VI
(Analysis of Impacts) of the proposed rule ($68), the cost to
respondents would be $43,277,240 (636,430 x $68).

                                     Table 7.--OMB Control Number 0910-0636
----------------------------------------------------------------------------------------------------------------
                                          Number of
 21 CFR Sections       Number of        Responses Per       Total Annual        Hours per         Total Hours
                      Respondents         Respondent         Responses           Response
----------------------------------------------------------------------------------------------------------------
Reports of                        50                250             12.500                  2             25,000
 serious adverse
 drug events (21
 U.S.C. 379aa((b)
 and (c))
----------------------------------------------------------------------------------------------------------------
Total                                                                                25,000
----------------------------------------------------------------------------------------------------------------

    Based on the average hourly wage as calculated in section VI
(Analysis of Impacts) of the proposed rule ($68), the cost to
respondents would be $1,700,000 (25,000 x $68).

B. Capital Costs

    As explained in section VI (Analysis of Impacts) of this document,
total one-time costs to industry under this rule would be between $4.5
million to $5.6 million; most of these costs would be for changing
SOPs, setting up systems for submissions, and acquiring an electronic
certificate. Industry would also incur annual costs of between $133,320
to $139,380 for Internet upgrades and to maintain electronic
certificates.
    The information collection provisions of this proposed rule have
been submitted to OMB for review. Interested persons are requested to
fax comments regarding information collection by (see DATES section of
this document), to the Office of Information and Regulatory Affairs,
OMB. 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: FDA Desk Officer,
FAX:<PHONE_NUMBER>, or e-mailed to<EMAIL_ADDRESS>All
comments should reference the title of this rule and include the FDA
docket number found in brackets in the heading of this document.

VIII. Federalism

    FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the rule does not contain policies that have substantial direct effects
on the States, on the relationship between the National Government and
the States, or on the distribution of power and responsibilities among
the various levels of government. Accordingly, the agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.

IX. Request for Comments

    Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
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.

List of Subjects

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.

21 CFR Part 314

    Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 310,
314, and 600 be amended as follows:

PART 310--NEW DRUGS

    1. The authority citation for 21 CFR part 310 continues to read as
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262,
263b-263n.

    2. Section 310.305 is amended by:
    a. Removing the word ``shall'' each time it appears and by adding
in its place the word ``must'';
    b. Adding alphabetically in paragraph (b) the definition of
``Individual case safety report (ICSR)'';
    c. Revising paragraph (c) introductory text, paragraph (c)(1)(i),
and the second sentence of paragraph (c)(3) introductory text; removing
the last sentence in paragraph (c)(2), and removing and reserving
paragraph (c)(4);
    d. Revising paragraph (d); and
    e. Redesignating paragraphs (e) through (g) as paragraphs (f)
through (h), adding a new paragraph (e), revising newly redesignated
paragraph (f), and in newly redesignated paragraph (g)(1) remove
``(c)(4)'' and add in its place ``(c)(3)'' to read as follows:

Sec.  310.305  Records and reports concerning adverse drug experiences
on marketed prescription drugs for human use without approved new drug
applications.

* * * * *
    (b) * * *
    Individual case safety report (ICSR). A description of an adverse
drug experience related to an individual patient or subject.
    (c) Reporting requirements. Each person identified in paragraph
(c)(1)(i) of this section must submit to FDA adverse drug experience
information as described in this section. Except as provided in
paragraph (e)(2) of this section, 15-day ``Alert reports'' and followup
reports, including ICSRs and any attachments, must be submitted to the
agency in electronic format as described in paragraph (e)(1) of this
section.
    (1) Postmarketing 15-day ``Alert reports''. (i) Any person whose
name appears on the label of a marketed prescription drug product as
its manufacturer, packer, or distributor must report to FDA each
adverse drug experience received or otherwise obtained that is both
serious and unexpected as soon as possible, but no later than 15
calendar days from initial receipt of the information by the person
whose name appears on the label. Each report must be accompanied by the
current content of labeling in electronic format unless it is already
on file at FDA.
* * * * *
    (3) * * * If a packer or distributor elects to submit these adverse
drug experience reports to the manufacturer rather than to FDA, it must
submit, by any appropriate means, each report to the manufacturer
within 5 calendar days of its receipt by the packer or distributor, and
the manufacturer must then comply with the requirements of this section
even if its name does not appear on the label of the drug product. * *
*
* * * * *
    (4) [Reserved]
* * * * *
    (d) Information reported on ICSRs. ICSRs include the following
information:
    (1) Patient information.
    (i) Patient identification code;
    (ii) Patient age at the time of adverse drug experience, or date of
birth;
    (iii) Patient gender; and
    (iv) Patient weight.
    (2) Adverse drug experience.
    (i) Outcome attributed to adverse drug experience;
    (ii) Date of adverse drug experience;
    (iii) Date of report;
    (iv) Description of adverse drug experience;
    (v) Description of relevant tests, including dates and laboratory
data; and
    (vi) Other relevant patient history, including preexisting medical
conditions.
    (3) Suspect medication(s).