[Federal Register Volume 79, Number 111 (Tuesday, June 10, 2014)]
[Rules and Regulations]
[Pages 33072-33092]
[FR Doc No: 2014-13480]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 314, 329, and 600

[Docket No. FDA-2008-N-0334]
RIN 9010-AF96

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

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or we) is amending 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 change will 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 amendments will be a key element in
harmonizing FDA's postmarketing safety reporting regulations with
international standards for the electronic submission of safety
information.

DATES: This rule is effective June 10, 2015.

FOR FURTHER INFORMATION CONTACT: For information concerning human drug
products: Jean Chung, Center for Drug Evaluation and Research (CDER),
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm.
7268, Silver Spring, MD 20993-0002,<PHONE_NUMBER>.
    For information concerning human biological products: Stephen
Ripley, Center for Biologics Evaluation and Research (CBER) (HFM-17),
Food and Drug Administration, 1401 Rockville Pike, Suite 200N,
Rockville, MD 20852-1448,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
    A. The Proposed Rule
    B. Changes to the Proposed Rule
II. Summary of the Final Rule
    A. Electronic Submission of Postmarketing Safety Reports
    B. Safety Reports Not Covered by the Final Rule

    C. Waivers
    D. Individual Case Safety Report (ICSR)--Definition and Required
Information
    E. Removal of Paper Format Provisions
    F. Section 745A of the FD&C Act and Electronic Format for
Submissions
    G. Miscellaneous Changes
III. Comments on the Proposed Rule
    A. Safety Reports Covered
    B. FDA Web-Based Submission Portal
    C. Waivers
    D. ICSR Submissions
    E. International Harmonization
    F. Technical Specifications
IV. Legal Authority
V. Environmental Impact
VI. Analysis of Impacts
VII. Paperwork Reduction Act of 1995
    A. Reporting Costs
    B. Capital Costs
VIII. Federalism
IX. Reference

I. Introduction

    In the Federal Register of August 21, 2009 (74 FR 42184), FDA
published a proposed rule to require that persons subject to mandatory
postmarketing safety reporting requirements for human drug or
biological products submit safety reports in an electronic format that
the Agency can process, review, and archive.
    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.
Since 2001, many companies have voluntarily submitted reports for drug
and nonvaccine biological products to the Agency in electronic format.
Data from both the electronic and paper reports are entered into the
FDA Adverse Event Reporting System (FAERS) database. FAERS is a
computerized information database designed to support FDA's
postmarketing safety surveillance program for drug and nonvaccine
biological products. The FAERS database is used to store and analyze
data received in postmarketing safety reports. Safety reporting data
submitted on paper is first converted into an electronic format before
being entered into FAERS.\2\ In September 2012, the FAERS database
replaced the previously used Adverse Event Reporting System (AERS)
database described in the preamble to the proposed rule (74 FR 42184 at
42185). The transition to the FAERS database has been an important step
in improving FDA's postmarketing surveillance capabilities. FAERS
supports greater functionality and more sophisticated pharmacovigilance
tools that enhance FDA's ability to analyze safety information.
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    \1\ For purposes of this preamble, the term ``adverse drug
experience'' includes an ``adverse experience'' associated with use
of a human drug or biological product.
    \2\ Additional information regarding the FAERS database may be
found at http://www.fda.gov/cder/aers/default.htm.
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    The proposed rule proposed that use of an electronic format be
mandatory for the submission of all required postmarketing safety
reports for human drug and biological products, including vaccines,\3\
a change to improve the Agency's systems for collecting and analyzing
these reports.
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    \3\ Data from postmarketing safety reports for vaccines is
entered into the Vaccine Adverse Event Reporting System (VAERS). The
VAERS database is used to store and analyze data received in
postmarketing safety reports for vaccines.
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A. The Proposed Rule

    In the preamble to the proposed rule (74 FR 42184 at 42187 to
42189), we set forth in detail the rationale for requiring electronic
submission of postmarketing safety reports. Receiving postmarketing
safety reports in electronic format will expedite access to safety
information and facilitate international harmonization and exchange of
this information. This, in turn, will lead to more efficient reviews of
safety data and will 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 will recognize a significant cost
savings by converting the safety reporting system from a paper
submission process to a predominantly all-electronic system that will
increase the accuracy of information and reduce the need for manual
data entry. We also believe this change will benefit industry by
eliminating time and costs associated with submitting paper reports.
    In the proposed rule, FDA proposed revising Sec. Sec.  310.305,
314.80, 314.98, and 600.80 (21 CFR 310.305, 314.80, 314.98, and 600.80)
to require that manufacturers, packers, and distributors, and
applicants 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, submit postmarketing safety reports (i.e.,
individual case safety reports (ICSRs) and any ICSR attachments) to the
Agency in an electronic format that FDA can process, review, and
archive. We stated that the proposal would apply to all postmarketing
safety reports 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 implemented in the future. (The preamble to the proposed rule
(74 FR 42184 at 42185 to 42186) describes current postmarketing safety
reporting requirements.) We also proposed revising Sec.  600.81 (21 CFR
600.81) to require the electronic submission of biological lot
distribution reports.
    The preamble to the proposed rule (74 FR 42184 at 42186 to 42187)
also discussed the Dietary Supplement and Nonprescription Drug Consumer
Protection Act (Public Law 109-462), enacted on December 22, 2006,
which amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act)
to create a new section 760 (21 U.S.C. 379aa), entitled ``Serious
Adverse Event Reporting for Nonprescription Drugs.'' As noted in the
preamble, section 760 of the FD&C Act requires manufacturers, packers,
or distributors whose name appears on the label of nonprescription
(over-the-counter or OTC) human drug products marketed without an
approved application to report to FDA serious adverse events associated
with their products. It does not apply to OTC drug products marketed
under applications approved under section 505 of the FD&C Act (21
U.S.C. 355), which are subject to the reporting requirements under
Sec.  314.80, as are all other drugs marketed under approved NDAs or
ANDAs.\4\ The requirement went into effect in December 2007, and to
assist entities in complying with the requirements, FDA issued a
guidance for industry entitled ``Postmarketing Adverse Event Reporting
for Nonprescription Human Drug Products Marketed Without an Approved
Application'' (available on

FDA's Web site at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm). In the
preamble to the proposed rule, we requested comment on whether to
require the electronic submission of postmarketing safety reports
required by section 760 of the FD&C Act (referred to in this document
as section 760 reports). We noted that our decision would be informed
by public comments received and our experience with the submission of
these reports to date.
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    \4\ Section 760 of the FD&C Act provides for mandatory safety
reporting for nonprescription human drug products not subject to
NDAs or ANDAs. Accordingly, the requirements apply to all OTC drug
products marketed without an approved application, including those
marketed under the OTC Drug Monograph Review process (whether or not
subject to a final monograph), those marketed outside the monograph
system, and including those that have been discontinued from
marketing but for which a report of an adverse event was received.
These reporting requirements became effective December 22, 2007.
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    The proposed rule stated that FDA would periodically issue guidance
on how to provide the electronic submissions (e.g., method of
transmission, media, file formats, preparation, and organization of
files). Currently, 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 (EU), Japan, and the United
States. The proposal reaffirmed our intention to continue to rely on
ICH standards while also providing other options for providing
electronic submissions to FDA.
    In the preamble to the proposed rule, we explained that applicants,
manufacturers, packers, and distributors had been voluntarily
submitting postmarketing safety reports for drugs and nonvaccine
biological products in electronic format by sending the reports to FDA
either through FDA's Electronic Submission Gateway (ESG) or on physical
media (e.g., CD-ROM (sent by mail).\5\ The ESG is the central
transmission point for sending information electronically to FDA. Among
other things, the ESG allows ICH-compatible postmarketing safety report
submissions to be transmitted directly from the company's database to
FDA.\6\ The direct database-to-database submissions may include ICSRs,
any ICSR attachments, and descriptive information. Once received
through the ESG, the ICSRs for drug and nonvaccine biological products
are downloaded into the FAERS database. FDA has encouraged electronic
submission of ICSRs because it is a cost-effective and efficient
alternative to paper-based reporting, particularly for companies
submitting large numbers of ICSRs. In addition, electronic submission
of ICSRs enhances global pharmacovigilance by facilitating electronic
transmission and exchange of appropriate information from ICSRs among
regulatory bodies and regulated entities through use of common data
elements and transmission standards.
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    \5\ FDA expects that, in the future, all electronic submissions
to the Agency will be sent through the ESG and that use of physical
media (e.g., CD-ROM) for such submissions will be phased out.
    \6\ ICH data elements for postmarketing safety reports are
available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129399.pdf.
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    In the preamble to the proposed rule, we also explained that we are
developing a ``Web-based submission portal'' to collect and process
safety information for FDA-regulated products. We anticipated that the
Web-based submission portal would allow the secure electronic
submission of postmarketing ICSRs directly into FDA's FAERS database
once information was entered into a ``Web-based electronic form.'' We
stated that the Web-based submission portal would allow submission of
ICSRs consistent with ICH standards and could be used as an alternative
method for reporting adverse drug experiences to FDA electronically. We
noted that the Web-based system would be particularly useful for
entities that submit a small number of safety reports because it would
create a simpler and more efficient mechanism for reporting that would
not require an internal database that is compatible with the ICH-based
direct transmission system. (See section II.A for further discussion of
the Web-based submission portal.)
    Because in certain rare circumstances electronic submission of
safety reports may not be feasible, we proposed (in Sec. Sec.
310.305(e)(2), 314.80(g)(2), and 600.80(g)(2)) to allow for the
submission of requests for a temporary waiver from the electronic
format requirement and stated that waivers would be granted on a
limited basis for good cause shown. We requested comments on
circumstances under which a waiver should be granted. We stated that
guidance would be issued describing the procedures for submitting a
waiver request. Elsewhere in this issue of the Federal Register, we are
announcing the availability of a draft guidance entitled ``Providing
Submissions in Electronic Format--Postmarketing Safety Reports'' (the
postmarketing safety reports guidance) (available on FDA's Web site at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm). It is intended to assist persons required to
submit postmarketing safety reports in complying with the final rule.
In addition, the draft guidance addresses procedures for submitting
waiver requests and other information.
    We proposed to delete the specific references to paper reporting
forms in Sec. Sec.  310.305, 314.80, and 600.80. Because the paper
reporting forms would no longer be used, we proposed to add a list of
the reportable elements to proposed Sec. Sec.  310.305(d), 314.80(f),
and 600.80(f). The list of reportable elements in the proposed rule was
derived from the elements included in Form FDA 3500A, the paper
reporting form. Moreover, the obligation to provide all applicable
information described in the proposed rule would be the same as the
obligation to complete Form FDA 3500A and VAERS-1. To facilitate the
shift away from the paper reporting forms, we also proposed to adopt a
generic term for the safety reporting vehicle: Individual case safety
report (ICSR). Proposed Sec. Sec.  310.305(b) and 314.80(a) define an
ICSR as ``a description of an adverse drug experience related to an
individual patient or subject.'' Proposed Sec.  600.80(a) defines ICSR
as ``a description of an adverse experience related to an individual
patient or subject.''

B. Changes to the Proposed Rule

    We received seven submissions containing comments on the proposed
rule. Several commenters expressed support for requiring electronic
submission of postmarketing safety reports, agreeing that it would help
FDA to more rapidly review safety reports and identify emerging safety
issues. Two commenters also expressed support for requiring the
electronic submission of safety reports required by section 760 of the
FD&C Act; no commenters opposed this requirement for the section 760
reports. Commenters also requested clarification of certain terms and
requirements in the proposed rule. We address all of the comments in
greater detail in section III.
    After considering the comments and based on our experience with
postmarketing safety reporting, we have concluded that certain
revisions to the proposed rule are appropriate. However, we note that
the provisions applicable to safety reporting under Sec. Sec.  310.305,
314.80, and 600.80 are largely unchanged from the proposed rule.
    We have concluded that the electronic submission requirement should
extend to safety reports required by section 760 of the FD&C Act.
Therefore, the final rule adds part 329 (21 CFR part 329), entitled
``Nonprescription Human Drug Products Subject to Section 760 of the
Federal Food, Drug, and Cosmetic Act'' to chapter 21 of the Code of
Federal

Regulations to address the safety reporting requirements of section 760
of the FD&C Act described in section I.A. This addition responds to the
two comments received on this issue, both of which supported requiring
the electronic submission of section 760 reports. It also reflects
FDA's determination that the electronic submission requirement should
extend to these safety reports in furtherance of FDA's goal to more
quickly review postmarketing safety reports and identify emerging
safety issues.
    The final rule adds new Sec.  329.100 to require the electronic
submission of section 760 reports. Section 329.100(a) states that
safety reports required by section 760 of the FD&C Act must be
submitted to FDA in electronic format. Section 329.100(b) explains that
for purposes of safety reporting under section 760, an ICSR constitutes
the ``MedWatch Form'' (the common name for Form FDA 3500A) required to
be submitted in section 760(d) of the FD&C Act, and sets forth the
elements that are reported in an ICSR under section 760. As noted
previously in this document and in the preamble to the proposed rule,
we have adopted the term ``individual case safety report'' (ICSR)
because we will no longer be using the paper reporting forms for
mandatory postmarketing safety reporting. New Sec.  329.100(c)(1)
states that the submissions must be in an electronic format that FDA
can process, review, and archive; Sec.  329.100(c)(2) provides for a
good-cause waiver; and Sec.  329.100(d) addresses patient privacy. All
of these provisions are analogous to the provisions in this final rule
for reports submitted under Sec. Sec.  310.305, 314.80, and 600.80.
    The final rule revises the proposed provisions entitled ``Patient
privacy'' (in final Sec. Sec.  310.305(f), 314.80(i), and 600.80(j)) to
state, ``the applicant should assign a unique code for identification
of the patient.'' \7\ This addresses a comment expressing concern that
the proposed rule was confusing because it used two different terms to
refer to the code that must be assigned to protect patient privacy.
Section 329.100(d) uses the revised language.
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    \7\ The revised language in Sec.  600.80(j) applies only to
nonvaccine biological products. ICSRs for vaccines should not use a
patient identification code but should continue to include the
patient's name (Sec.  600.80(g)).
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    On our own initiative, we have made revisions that are described as
follows. The final rule adds a definition for the term ``ICSR
attachments'' to Sec. Sec.  310.305(b), 314.80(a), and 600.80(a). In
Sec. Sec.  310.305(b) and 314.80(a), ICSR attachments are defined as
``documents related to the adverse drug experience described in an
ICSR, such as medical records, hospital discharge summaries, or other
documentation.'' In Sec.  600.80(a), ICSR attachments are defined as
``documents related to the adverse experience described in an ICSR,
such as medical records, hospital discharge summaries, or other
documentation.''
    The final rule revises the proposed provisions addressing waivers
in proposed Sec. Sec.  310.305(e)(2), 314.80(g)(2), and 600.80(g)(2).
The final rule deletes the statement that if the Agency grants a
waiver, the person who requested the waiver must submit the required
reports on paper within the required time periods and that FDA intends
to issue guidance on how to provide the paper submission. This
statement has been deleted so that the rule does not specify that
safety reports that cannot be submitted in electronic format must be
submitted on paper. We recognize that alternate formats for safety
reports, other than paper, such as email or fax, may be appropriate
when a waiver of the electronic submission requirement is granted. We
will specify an acceptable alternate format at the time the waiver is
granted. The final rule also modifies the language indicating that
procedures for how to request waivers will be set forth in guidance.
The proposed rule stated, ``Procedures for how to request waivers of
this requirement will be set forth in guidance.'' The final rule
states, ``FDA will issue guidance on requesting a waiver of the
requirements [for electronic submission].'' We have made this change to
indicate that the guidance addressing waivers may include information
on other aspects of the waiver provision, such as circumstances under
which FDA may grant waivers, not just the procedures for how to request
waivers. (The waiver provision for biological products has been
finalized in Sec.  600.80(h)(2).) Section 329.100(c)(2), applicable to
section 760 reports for nonprescription products marketed without an
approved application, contains this revised language on waivers. It is
important to note that the waiver referred to in the final rule (as in
the proposed rule) pertains only to the electronic format requirements.
It is not a waiver from the underlying safety reporting requirement.
    On our own initiative, we have made additional changes to the
provisions addressing patient privacy. The proposed provisions entitled
``Patient privacy'' (in proposed Sec. Sec.  310.305(f), 314.80(i), and
600.80(i)) state that the preferred methodology for determining the
identification code will be set forth in guidance. FDA does not believe
that it is necessary to identify specific elements in the final rule
for which we will be providing technical guidance or specifications.
FDA currently provides and will continue to provide technical guidance
and specifications for many different aspects of electronic ICSR
submission. Accordingly, we are deleting that language from final
Sec. Sec.  310.305(f), 314.80(i), and 600.80(j). However, for drug and
nonvaccine biological products, we recommend that no identifying
information, such as initials or birthdate, be used as part of the
patient identification code. At the same time, under new Sec.
600.80(g), ICSRs for vaccine products will continue to include the
patient's name.
    In the patient privacy provisions, we proposed that the name of the
reporter not be included when the reporter is also the patient. The
proposed provision stated that the submitter should include the name of
the reporter from whom the information was received, unless the
reporter is the patient. FDA is not finalizing the proposal because we
have concluded that those submitting mandatory safety reports should
include the name of the reporter (in the reporter section of the ICSR),
even when the reporter is the patient. It is important for FDA to have
the name of the reporter so that we may contact the reporter, if
necessary, to obtain followup information about the adverse event
reported. To make clear that the name of the reporter should be
provided (in the initial reporter information section of the ICSR),
even when the reporter is the patient, we are amending the patient
privacy provisions in the final rule to state, ``the [submitter] should
include the name of the reporter from whom the information was received
as part of the initial reporter information, even when the reporter is
the patient'' (Sec. Sec.  310.305(f), 314.80(i), 329.100(d), and
600.80(j)). FDA regulations prohibit the release of the names of
patients, health care professionals, hospitals, and geographical
identifiers in adverse event reports to the public, so it is unlikely
that the patient's privacy will be compromised if the patient's name is
provided in situations where the patient is the reporter.
    The final rule modifies the language in proposed Sec.  600.81(b)(1)
describing the electronic format requirement for biological product lot
distribution reports so that it reflects the language used in analogous
provisions (Sec. Sec.  310.305(e)(1), 314.80(g)(1), 329.100(c)(1), and
600.80(h)(1)).
    As described later in this section, the final rule also makes some
revisions to the proposed provisions that set forth the reportable
elements included in an ICSR. Changes to the language

describing certain elements, including the addition of descriptive
phrases, have been made to clarify to what information those elements
refer. The final rule also adds a new Sec.  600.80(g) and adds certain
elements to proposed Sec. Sec.  310.305(d), 314.80(f), and 600.80(f) to
more accurately describe the information currently reported on the
VAERS-1 form and Form FDA 3500A. Accordingly, Sec. Sec.  310.305(d),
314.80(f), 329.100(b), and 600.80(f) list ICSR elements, derived from
Form FDA 3500A, for drug and nonvaccine biological products. Section
600.80(g) in the final rule lists ICSR elements for vaccine products
derived from the VAERS-1 form.
    The new Sec.  600.80(g) has been added to the final rule to capture
the information reported on the VAERS-1 form that was inadvertently
omitted from the proposed rule. Section 600.80(f) applies only to
nonvaccine biological products. Section 600.80(g) in the final rule
lists ICSR elements for vaccines that are derived from the VAERS-1
form. The list of elements in Sec.  600.80(g) (for vaccine products) is
largely the same as the list of elements for nonvaccine biological
products, but there are some variations, including certain additional
elements applicable only to safety reporting for vaccine products.
Reporting elements that have been included for vaccine ICSRs that are
not applicable to ICSRs for nonvaccine biological products include,
among others, patient name (in place of patient identification code),
birth weight for children under 5, time of adverse experience, illness
at the time of vaccination, anatomical site of vaccination, number of
previous vaccine doses, time of vaccination, other vaccine(s)
administered in the 4 weeks before the vaccination date, name of the
person who administered the vaccine, and name of the responsible
physician at the facility where the vaccine was administered. This
information is currently reported on the VAERS-1 form and is important
for FDA to evaluate adverse experiences associated with the
administration of vaccines. In addition, because Sec.  600.80(g) does
not include patient identification code as a reporting element, FDA has
revised Sec.  600.80(c)(2)(ii)(A)(2) and (A)(4), which describe how to
reference and index ICSRs in periodic reports, to note that ICSRs for
nonvaccine biological products should be referenced and indexed by
patient identification code, whereas ICSRs for vaccines should be
referenced and indexed by unique case identification number.
    The final rule removes from proposed Sec. Sec.  310.305(d),
314.80(f), and 600.80(f) the element requiring applicants to report
information on whether the initial reporter also sent a copy of the
report to FDA. FDA does not often use that information to identify
duplicate reports, and including that information is not consistent
with international electronic reporting standards. The final rule adds
to all sections that contain reporting elements the following elements
to be reported: (1) Whether the report is a 15-day ``Alert report'' and
(2) whether the ICSR is an initial report or a followup report. These
two elements replace the element requiring the type of report (e.g.,
15-day, periodic, followup). We believe that it is clearer to represent
this information with two separate elements. The final rule adds to
Sec. Sec.  310.305(d), 314.80(f), and 600.80(f) the element requiring
information on whether the product is a combination product as defined
under Sec.  3.2(e) (21 CFR 3.2(e)).\8\ The final rule adds to
Sec. Sec.  310.305(d), 314.80(f), and 600.80(f) the element ``whether
the product is a prescription or nonprescription product.'' Section
329.100(b) also lists ``whether the product is a prescription or
nonprescription product'' as an element to be included in an ICSR. Even
though Sec.  310.305 only applies to prescription products and Sec.
329.100 only applies to nonprescription products, for consistency, we
use the same language in all sections to describe the information to be
provided. The final rule removes from proposed Sec.  310.305(d),
``Basis for marketing if nonapplication product'' because we are able
to obtain that information based on the status of the drug as a
prescription product and whether a drug application number is provided.
The final rule adds to the ICSR elements for each product type (e.g.,
drug, nonvaccine biological product, vaccine) ``unique case
identification number,'' which must be the same in the initial report
and any subsequent followup reports. The unique case identification
number is different from the ``unique code [used] for identification of
the patient.'' The ``unique case identification number'' replaces the
``Manufacturer Report Number'' used on Form FDA 3500A and VAERS-1.
Using a unique case identification number (that is the same in the
initial ICSR and any followup reports) allows FDA to link the initial
ICSR with any followup reports in the FAERS or VAERS database. This
will allow FDA to track an individual case over its life cycle.
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    \8\ For purposes of postmarketing safety reporting, combination
product, under Sec.  3.2(e), includes: (1) A product comprised of
two or more regulated components, i.e., drug/device, biological
product/device, drug/biological product, or drug/device/biological
product, that are physically, chemically, or otherwise combined or
mixed and produced as a single entity and (2) two or more separate
products packaged together in a single package or as a unit and
comprised of drug and device products, device and biological
products, or biological and drug products.
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II. Summary of the Final Rule

A. Electronic Submission of Postmarketing Safety Reports

    The final rule revises current 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. As addressed in
section I.B of this document, the final rule also adds part 329 to
address safety reports required by section 760 of the FD&C Act. Section
329.100 requires that reports required to be submitted to the Agency
under section 760 of the FD&C Act be submitted in an electronic format
that FDA can process, review, and archive.
    Under the final rule, the following reports must be submitted to
FDA in an electronic format: Postmarketing 15-day Alert report ICSRs
and any ICSR attachments; periodic adverse (drug) experience reports
(including the ICSRs, any ICSR attachments, and the descriptive
information portion); and section 760 reports. A separate ICSR is to be
submitted for each individual patient report of an adverse drug
experience, just as separate paper forms have been submitted for each
individual patient report of an adverse drug experience. Information on
the formats the Agency is able to process, review, and archive is
described in FDA guidance and associated technical specifications
documents available on FDA's Web site.
    For marketed products with an approved application, manufacturers,
packers, or distributors that do not hold the application 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 reports directly to FDA, they
are required to do so in electronic format. If they choose to report to
the applicant, they may submit the report in any format acceptable to
the reporter and applicant. The applicant, however, is required to use
electronic reporting when it subsequently reports the information to
FDA. Similarly, for marketed

prescription drug products without an approved application, initial
safety reports submitted to the manufacturer by packers and
distributors under Sec.  310.305 may be sent in any format agreeable to
the reporter and the manufacturer, but all safety reports submitted to
FDA must be in electronic format. Under section 760 of the FD&C Act, a
retailer whose name appears on the label of a nonprescription (OTC)
drug product marketed in the United States without an approved
application, as a distributor, may, by agreement, authorize the
manufacturer or packer of the nonprescription drug to submit the
required reports to FDA (as long as the retailer directs to the
manufacturer or packer all adverse events associated with the drug that
are reported to the retailer as specified in section 760). The retailer
may direct serious adverse event reports to the manufacturer or packer
in any agreed-upon format. However, the manufacturer or packer must
then send the required reports to FDA in an electronic format that the
Agency can process, review, and archive.
    This rule will apply to any new postmarketing safety reports for
drug or biological products that are implemented in the future (e.g.,
once finalized, new postmarketing safety reports in the proposed rule
to amend safety reporting requirements published in the Federal
Register of March 14, 2003, 68 FR 12406). The rule also revises Sec.
600.81, requiring the electronic submission of biological lot
distribution reports.\9\ The specific references to submission of
postmarketing safety reports in paper format in Sec. Sec.  310.305,
314.80, 600.2, and 600.80 have been deleted, and language has been
added to these sections which states that FDA will issue guidance on
how to provide the electronic submissions (e.g., method of
transmission, media, file formats, preparation, and organization of
files).
---------------------------------------------------------------------------

    \9\ As noted in Sec.  600.81, FDA intends to issue guidance
addressing electronic submission of these reports.
---------------------------------------------------------------------------

    In the proposed rule, we stated that we were developing a Web-based
submission portal (for submission of reports to FAERS) that we believed
might be preferred by entities that submit a small number of safety
reports. The Safety Reporting Portal (SRP) (available at http://www.safetyreporting.hhs.gov) allows the secure electronic submission of
ICSRs for drug and nonvaccine biological products directly into the
FAERS database once information is typed into the Web-based electronic
form. The SRP creates a simple and efficient mechanism for electronic
reporting that does not require an internal ICH-compatible database. As
described in the preamble to the proposed rule, use of the SRP does
however require some administrative support to manually enter
information for the ICSRs into a Web-based form.
    To assist entities that submit a small number of safety reports for
vaccines, FDA has made available an eSubmitter tool. The eSubmitter
tool is a stand-alone application that can be downloaded free of charge
from FDA's Web site at http://www.fda.gov/forindustry/fdaesubmitter.
The eSubmitter application appears as a fillable form, and once the
appropriate fields are filled in, an ICSR in electronic format is
generated that can be transmitted through the ESG into the VAERS
database. We believe that the eSubmitter tool generally offers the same
benefits as the SRP. As noted in Sec.  600.80(h), FDA will issue
guidance providing further information about the electronic submission
of vaccine reports.

B. Safety Reports Not Covered by the Final 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. We anticipate that this final rule will permit FDA to
manage these postmarketing safety reports more efficiently. The final
rule only addresses electronic submission of postmarketing safety
reports for drugs and biological products and does not apply to
submission of the following reports:
     Investigational new drug application (IND) safety reports
(Sec.  312.32 (21 CFR 312.32));
     Safety update reports for drugs (Sec.  314.50(d)(5)(vi)(b)
(21 CFR 314.50(d)(5)(vi)(b));
     Approved NDA and BLA annual reports (Sec. Sec.
314.81(b)(2) and 601.28 (21 CFR 314.81(b)(2) and 601.28));
     Biological product deviation reports (BPDRs) (Sec. Sec.
600.14 and 606.171 (21 CFR 600.14 and 606.171));
     Reports of complications of blood transfusion and
collection confirmed to be fatal (Sec. Sec.  606.170(b) and 640.73 (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 (PHS Act) (42 U.S.C. 264)
(Sec.  1271.350(a) (21 CFR 1271.350(a)); and
     NDA-field alert reports (Sec.  314.81(b)(1) (21 CFR
314.81(b)(1)).

C. Waivers

    Although this final rule requires that all postmarketing safety
reports be submitted to FDA in electronic format, new Sec. Sec.
310.305(e)(2), 314.80(g)(2), 329.100(c)(2), 600.80(h)(2), and
600.81(b)(2) allow for a temporary waiver from the electronic format
requirement for ``good cause'' shown.\10\ Details for submitting waiver
requests, such as where to send the request and any supporting
information, are provided in the postmarketing safety reports guidance
issued today in conjunction with this final rule. When a temporary
waiver has been granted, FDA intends to specify an acceptable alternate
format for submitting the safety reports. FDA anticipates that
temporary waivers of the requirement to submit postmarketing safety
reports to the Agency in electronic format will be needed only in rare
circumstances.
---------------------------------------------------------------------------

    \10\ Waiver requests under Sec. Sec.  600.80(h)(2) and
600.81(b)(2) must be submitted in accordance with Sec.  600.90.
---------------------------------------------------------------------------

    Companies experiencing technical difficulties with transmission of
their electronic submissions to FDA should consult FDA for technical
assistance rather than submitting a waiver request. Companies that
normally use the direct database-to-database method to submit reports
to FDA could use the SRP as a backup method for FAERS submissions and
the eSubmitter tool as a backup method for VAERS submissions during
short-term, temporary outages.

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

    In this final rule, as in the proposed rule, the term ``individual
case safety report'' (ICSR) is used to describe the information
contained in either an initial or a followup report of an individual
adverse drug experience, reported on a Form FDA 3500A, on a Council for
International Organizations of Medical Sciences (CIOMS) I form, on a
VAERS-1 form, or in electronic format. Because we are requiring that
all postmarketing safety reports be submitted in electronic format, we
proposed this term to describe the safety reporting vehicle
generically, rather than by reference to the associated paper form. In
addition, this term in now commonly used in international electronic
reporting standards (e.g., ICH E2B, Health Level 7 (HL7)) in reference
to such reports.
    Accordingly, as proposed, Sec. Sec.  310.305(b) and 314.80(a) have
been revised to define an ICSR as a description of an adverse drug
experience related to an individual

patient or subject, and Sec.  600.80(a) has been revised to define an
ICSR as a description of an adverse experience related to an individual
patient or subject. Because the items of information to be reported
were specified on the paper reporting forms that will no longer be used
for reports covered under this rule, we have added a list of the
reportable elements to the regulations. Accordingly, Sec. Sec.
310.305(d), 314.80(f), 329.100(b), 600.80(f), and 600.80(g) provide
detailed lists of specific elements (in five broad categories for
nonvaccine products and seven broad categories for vaccine products)
that are to be reported in an ICSR, derived from the associated paper
forms. The five categories applicable to all products, including
vaccines, and examples of some of the types of information in each
category, are as follows:
     Patient information (e.g., age, gender);
     Information about the adverse experience (e.g., date and
description of the adverse drug experience);
     Information about the suspect medical product (e.g., drug
name, dose, indication, National Drug Code (NDC) number);
     Information about the initial reporter (e.g., name and
contact information); and
     Information about the drug's applicant or manufacturer or
responsible person (e.g., name and contact information)

In addition, the two categories applicable to vaccine products only are
as follows:

     Information about other vaccine(s) administered in the
previous 4 weeks; and
     Information on the facility and personnel where the
vaccine was administered (e.g., name of person who administered
vaccine, name of responsible physician and facility where the vaccine
was administered).
    Though there are minor wording differences, the list of information
to be reported is derived from the information reflected on Form FDA
3500A and VAERS-1 for postmarketing reporting for drugs and biological
products. Codification of the ICSR reporting requirements is not
intended to change the 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 Sec. Sec.  310.305(d), 314.80(f),
329.100(b), 600.80(f), or 600.80(g) is the same as the obligation to
complete Form FDA 3500A or VAERS-1.

E. Removal of Paper Format Provisions

    We believe that it is no longer necessary to describe procedures
for paper format submissions in the regulations because we anticipate
that a paper format will be used on a limited basis, if at all.
Accordingly, as proposed, this final rule removes from the 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 have deleted in
Sec. Sec.  310.305(d), 314.80(f), and 600.80(f) the provisions
specifically describing paper submissions and replaced them with a
paragraph (Sec. Sec.  310.305(e)(1), 314.80(g)(1), and 600.80(h)(1)),
which states that ICSRs and any ICSR attachments must be submitted to
FDA in an electronic format that we can process, review, and archive.
Additional revisions to remove or modify references or provisions that
are specific to paper formats include the following:
     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 Form FDA 3500A, CIOMS I form, or
VAERS-1 form or to determine an appropriate alternative format for
voluntary submission in electronic format (Sec. Sec.  310.305(d)(1) and
(d)(3), 314.80(f)(1) and (f)(3), and 600.80(f)(1) and (f)(3));
     The reference to Form FDA 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));
     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));
     The requirement to submit adverse experience reports by
mail to CBER's mailing address (Sec.  600.2(a)) by deleting the phrase
``adverse experience reports'' from Sec.  600.2(a);
     The requirement to submit adverse experience reports by
mail to CDER's mailing address (Sec.  600.2(b)(2));
     The requirement to submit VAERS reports by mail to the
VAERS mailing address (Sec.  600.2(d)); and
     The requirement to submit distribution reports on
biological products by mail (Sec.  600.81) by deleting ``(see mailing
addresses in Sec.  600.2)'' from Sec.  600.81.
    As noted previously in this document, procedural and formatting
recommendations, if applicable to electronic submissions, will be set
forth in guidance.\11\
---------------------------------------------------------------------------

    \11\ We are also issuing a draft guidance today in conjunction
with this final rule. The draft guidance, when finalized, will
represent FDA's current thinking on certain topics pertaining to the
electronic submission of postmarketing safety reports in the context
of this rulemaking.
---------------------------------------------------------------------------

F. Section 745A of the FD&C Act and Electronic Format for Submissions

    Section 745A(a) of the FD&C Act (21 U.S.C. 379k-1), added by
section 1136 of the Food and Drug Administration Safety and Innovation
Act (Pub. L. 112-144), provides that submissions under section 505(b),
(i), or (j) of the FD&C Act or section 351(a) or (k) of the PHS Act
shall be submitted in such electronic format as specified by FDA in
guidance. In section 745A(a) of the FD&C Act, Congress granted explicit
statutory authority to FDA to implement the electronic format for
submissions requirement by guidance. This grant of authority, however,
does not preclude FDA from implementing such requirements by notice and
comment rulemaking (5 U.S.C. 553). At this time, even though we
conclude that certain submissions that are addressed in this final rule
are also within the scope of section 745A(a) of the FD&C Act, FDA has
determined that it is appropriate to amend the current regulations on
the submission of postmarketing safety reports to remove references to
paper submissions and to specify that such reports be submitted in an
electronic format that FDA can process, review, and archive. FDA may
consider, at a future date, whether certain electronic submission
requirements should be specified in guidance pursuant to section
745A(a) of the FD&C Act.

G. Miscellaneous Changes

    As proposed, the final rule amends 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'' has been removed
for editorial reasons. The final rule revises in Sec.  314.80(c)(2) the
paragraph designations that were not in correct format. We believe that
these minor changes clarify the regulations and make them easier to
read. The final rule, as proposed, also changes the term ``licensed
manufacturer'' to ``applicant'' in Sec. Sec.  600.80, 600.81, and
600.90.

    The mailing addresses for the submission of postmarketing safety
reports have been removed from Sec. Sec.  310.305(c), 314.80(c),
314.98(b), and 600.80(c) because this information is no longer
necessary in light of the requirement to submit safety reports
electronically.
    Final Sec.  310.305(c)(1)(i) requires the submission of a current
copy of the labeling in electronic format unless it is already on file
with FDA. Previously, under Sec.  310.305(c)(1)(i), each report was to
be accompanied by a copy of the labeling. However, if the Agency
already has the current labeling on file, we do not believe it is
necessary for a current copy of the labeling to be submitted with each
report.\12\
---------------------------------------------------------------------------

    \12\ For products subject to Sec.  310.305(c)(1)(i), a copy of
the labeling is submitted to FDA in Structured Product Labeling
(SPL) format as part of the electronic drug listing process. See the
guidance for industry ``Providing Regulatory Submissions in
Electronic Format--Drug Establishment Registration and Drug
Listing'' (May 2009) available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/default.htm and FDA's Web
site on Structured Product Labeling Resources at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm for
information on submitting labeling to FDA in electronic format.
---------------------------------------------------------------------------

    For products with approved applications, currently, reports for all
adverse experiences other than those submitted as 15-day Alert reports
or followup reports to 15-day Alert reports (i.e., reports of adverse
experiences that are both serious and expected or nonserious) are
required to be submitted as a batch as part of the postmarketing
periodic safety report for the reporting interval during which the
applicant received the report. Although the ICSRs may be generated at
any time from the beginning of the reporting interval through the date
that the periodic report is submitted to FDA, they are currently
retained by the applicant during this time period and submitted to FDA
in a single batch, along with the other (descriptive) portions of the
periodic report. The final rule includes language in Sec. Sec.
314.80(c)(2)(ii)(B) and 600.80(c)(2)(ii)(B) to give applicants the
option of submitting these ICSRs at any time up until the due date of
the periodic report, rather than waiting to submit them in a single
batch with the descriptive portion. All reports of adverse experiences
that are both serious and expected or nonserious that the applicant
received during the reporting interval must still be submitted to the
Agency by the time the descriptive portion is due for that period, but
the final rule permits them to be filed anytime up until the due date
of the periodic report, rather than in a single batch with the
descriptive portion of the periodic report. We have adopted this
change, as proposed, because we understand that many applicants prefer
this added flexibility of submitting the ICSRs on an ongoing basis.
    To protect patient privacy, names of individual patients are not to
be included in the patient identification portion of the ICSRs for drug
and nonvaccine biological products. We instead require that a unique
code be used for patient identification. As proposed, the final rule
removes from the provisions entitled ``patient privacy'' the language
specifying an eight character limit on the code. Although we also
proposed that the name of the reporter not be included when the
reporter is also the patient, we are not finalizing that proposal. FDA
has determined that it is important for us to have the name of the
reporter, even when the patient is the reporter, because it will allow
us to contact the reporter, if necessary, to obtain followup
information. Names of patients, health care professionals, hospitals,
and geographical identifiers in adverse drug experience reports are not
releasable to the public under FDA's public information regulations.
These same requirements addressing patient privacy have been included
in Sec.  329.100(d), applicable to reports required by section 760 of
the FD&C Act.
    As proposed, we have revised Sec. Sec.  310.305(c)(1)(i),
314.80(c)(1)(i), and 600.80(c)(1)(i) to state that 15-day Alert reports
must be submitted as soon as possible, but no later than 15 calendar
days from initial receipt of the information. FDA does not intend this
change to have any substantive effect. It is being made solely to
simplify the regulatory language and improve its readability.

III. Comments on the Proposed Rule

    We received written comments from three pharmaceutical companies,
two associations representing the drug and biologic industries, a law
firm representing a manufacturer of nonprescription drug products
marketed without approved applications, and an individual (seven
commenters total). A summary of the comments contained in the
submissions received, and our responses, follow.

A. Safety Reports Covered

    (Comment 1) In the preamble to the proposed rule, we requested
public comment on whether we should require the use of an electronic
format for reports of serious adverse events required by then newly
enacted section 760 of the FD&C Act for nonprescription human drug
products marketed without an approved application. Two commenters
supported requiring the use of an electronic format for the submission
of reports required by section 760 of the FD&C Act. No comments were
opposed to such a requirement.
    (Response) As discussed in section I.B, we agree that the
requirement that postmarketing safety reports be submitted
electronically should extend to safety reports required to be submitted
by section 760 of the FD&C Act. Electronic submission of safety reports
required to be submitted by section 760 of the FD&C Act will allow FDA
to process, review, and archive such reports more efficiently.
Therefore, as described previously in this document, we have added 21
CFR part 329 to cover nonprescription human drug products subject to
section 760 of the FD&C Act. Section 329.100 sets forth information to
be included in safety reports that are required to be submitted by
section 760 of the FD&C Act and requires that the reports be submitted
in an electronic format that FDA can process, review, and archive. As
with safety reports required by Sec. Sec.  310.305, 314.80, and 600.80,
Sec.  329.100 also includes a provision allowing requests for a
temporary waiver from the electronic submission requirement for good
cause. As noted in the preamble to the proposed rule, nonprescription
(OTC) drug products that are marketed under approved applications (NDAs
or ANDAs) are not covered under section 760 of the FD&C Act. Those
products are subject to the reporting requirements of Sec. Sec.  314.80
and 314.98.
    (Comment 2) One comment suggested that we develop an option to
allow IND safety reports to be submitted electronically. The comment
states that this option would reduce the burden for companies that must
use two different systems.
    (Response) The comment is beyond the scope of this rulemaking. This
rule addresses only the electronic submission of postmarketing safety
reports. Premarketing safety reports are transmitted directly to the
review division of FDA that has responsibility for review of the IND
and are not uploaded into the FAERS database.
    (Comment 3) Although this rulemaking does not apply to biological
product deviation reports (BPDRs), in the preamble to the proposed
rule, we requested comment on requiring the electronic submission of
BPDRs (required by Sec. Sec.  600.14 and 606.171) in the future. One
comment supported requiring the electronic submission of BPDRs and also
suggested that the

current Web-based form available for the voluntary electronic
submission of BPDRs be modified to allow more than 2,000 characters in
the event description field to allow a complete description of the
event.
    (Response) We appreciate the comment. As addressed in section II.F,
section 745A(a) of the FD&C Act provides that submissions under section
351(a) or (k) of the PHS Act, which include BPDRs, shall be submitted
in such electronic format as specified by FDA in guidance. The Agency
intends to address the implementation of section 745A(a) of the FD&C
Act separately. In the meantime, parties wishing to submit BPDRs
electronically are encouraged to do so through the existing Web-based
system. We note that the current electronic system for BPDR reporting
has been expanded to allow up to 3,999 characters for narrative
entries.
    (Comment 4) Two comments requested that we address the submission
of postmarketing safety reports for combination drug and device
products in the final rule. One comment noted specifically that
reporting requirements for drugs and biologics differ from the
reporting requirements of devices and therefore requested that we
provide further information on how to submit safety reports for drug
and device combination products.
    (Response) These comments are beyond the scope of this rulemaking.
This final rule requires electronic submission of required
postmarketing safety reports for drugs and biological products
(including vaccines). We note that on October 1, 2009, FDA published a
proposed rule entitled ``Postmarketing Safety Reporting for Combination
Products'' (74 FR 50744). When finalized, this new rule will clarify
the safety reporting requirements for combination products such as drug
and device combinations.
    (Comment 5) One comment noted that the preamble to the proposed
rule indicates that developments are underway for VAERS to receive
ICSRs for vaccines through FDA's ESG. The comment stated, however, that
no information is provided regarding how and when these submissions may
be made to VAERS.
    (Response) Modifications are still underway to permit VAERS to
receive ICSRs through FDA's ESG, which will facilitate the submission
of multiple reports without the need for manual data entry. FDA expects
that VAERS will be able to receive ICSRs through the ESG by the time
this final rule becomes effective.

B. FDA Web-Based Submission Portal

    In the preamble to the proposed rule, we explained that a ``Web-
based electronic submission portal'' was under development to allow the
secure electronic submission of postmarketing ICSRs directly into FDA's
AERS database once information is entered into a ``Web-based electronic
form.'' We noted that the Web-based submission portal would allow
electronic submission of ICSRs consistent with ICH standards and could
be used as an alternative method for reporting adverse drug experiences
to FDA electronically. We noted that this alternative electronic
reporting method would be particularly useful for entities that submit
a small number of safety reports because it would create a simpler and
more efficient mechanism for reporting that would not require an
internal database that is compatible with the ICH-based direct
submission system.
    (Comment 6) One comment requested clarification of the terms ``Web-
based submission portal'' and ``Web-based form,'' noting that both
terms are used in the preamble to the proposed rule.
    (Response) In the proposed rule, we used the term ``Web-based
submission portal'' (now referred to as the Safety Reporting Portal
(SRP)) to describe a Web-based system that any person subject to FDA's
postmarketing safety reporting requirements could use to submit ICSRs
to FDA electronically. (See section II.A for further discussion of the
SRP.) We used the term ``Web-based form'' to describe the on-screen
interface into which users would enter the ICSR data elements. Users
``complete'' the ICSR by filling in the appropriate fields in the Web-
based form and then submit the ICSR to the FAERS database through the
Web-based submission portal.\13\
---------------------------------------------------------------------------

    \13\ As described in section II.A, the eSubmitter tool will be
used instead of the SRP as an alternative method for the electronic
submission of vaccine ICSRs into the VAERS database.
---------------------------------------------------------------------------

    (Comment 7) One comment suggested that to eliminate any potential
barriers for small companies, no charge should be associated with use
of the Web-based system.
    (Response) There will be no charge for electronic submission of
safety reports to the FAERS database through the SRP. For submissions
to VAERS using the eSubmitter tool, however, a digital security
certificate will be necessary. These certificates allow users to sign
and encrypt documents for transmission, ensuring that any electronic
submissions are verifiable and secure. Digital certificates are
available through many third-party vendors. A certificate generally
lasts 1 to 3 years and typically costs $10 to $15. A digital
certificate is also necessary to comply with FDA's electronic
registration and listing requirements, so most companies already have
digital certificates and will not need to obtain one to use the
eSubmitter tool. Further information about digital security
certificates is available on FDA's Electronic Drug Registration and
Listing Instructions Web page at http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/ucm177328.htm.
    (Comment 8) One comment asked whether training or some type of
qualification will be required to submit ICSRs through the Web-based
system.
    (Response) The SRP creates a simpler mechanism for electronic
submission of safety reports. No special training or qualification will
be required. The information for the ICSR is entered into the Web-based
form and then submitted to FDA. However, prior to initial use of the
SRP, companies will need to contact the FAERS Electronic Submissions
Coordinator at<EMAIL_ADDRESS>to establish an account to submit
safety reports through the SRP. Having an SRP account allows for faster
data entry because certain fields will be pre-populated by information
from the user account. Having an account also allows users to save a
report and complete it later, allows users to see a list of reports
that have been submitted, and allows for followup submissions as more
information about the adverse drug experience becomes available.
Further information on submitting ICSRs through the SRP is included in
the postmarketing safety reports guidance.
    For vaccine products, the eSubmitter tool can be used, instead of
the SRP, as an alternative method for the electronic submission of
ICSRs to VAERS. The eSubmitter tool provides a user-friendly method for
submission of these reports, and no special training or qualification
will be necessary. Firms will, however, need to contact FDA's ESG Help
Desk to establish an ESG account and will need to obtain a digital
security certificate (as described in the previous response), if these
two steps have not already been completed to comply with FDA's
electronic drug registration and establishment listing requirements.
The first time firms submit a report to the VAERS database, they will
also need to contact the CBER Electronic Submissions Program at
<EMAIL_ADDRESS>    (Comment 9) One comment suggested that companies should be able to
use both the Web-based portal and the ESG

and should not have to choose one system.
    (Response) FDA will not limit companies to one method for creating
and transmitting ICSRs electronically to FDA. As described in this
document, FDA offers both the direct database-to-database method and
the SRP for submission of ICSRs into the FAERS database, and the direct
database-to-database method and eSubmitter tool for submission of ICSRs
into the VAERS database. FDA recommends that companies select the
submission method that best suits their needs to submit a given report.
    (Comment 10) One comment recommended that the Web-based portal
provide a receipt or acknowledgement indicating whether the submission
was successfully received or if the delivery failed. The comment noted
that this will allow companies to take appropriate followup action.
    (Response) When using the SRP to submit postmarketing safety
reports, users will receive electronic acknowledgement indicating
whether or not their submission was accepted into the FAERS
database.\14\ If notified that the submission was not accepted, users
should resubmit the safety report to ensure that FDA receives the
report. Further information about FAERS submission acknowledgement is
provided in the postmarketing safety reports guidance.
---------------------------------------------------------------------------

    \14\ Similarly, users submitting ICSRs for vaccines using the
eSubmitter tool will receive an electronic confirmation. Further
information about VAERS submission acknowledgement is provided in
guidance available at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
---------------------------------------------------------------------------

    (Comment 11) One comment stated that the Web-based portal should
accept ICH-compliant XML files that may be generated and submitted to
the Web-based portal and/or the ESG.
    (Response) The SRP allows for the submission of ICH-compliant
ICSRs. Once the data elements for the ICSR are entered into the Web-
based form and submitted to FDA, the SRP generates an XML file which is
then uploaded into the FAERS database (along with any ICSR attachments
that may be included). The ESG will continue to accept ICH-compliant
XML files. Similarly, for submission of vaccine reports, both the
eSubmitter tool and the direct database-to-database transmission method
generate ICH-compliant XML files that are submitted to FDA through the
ESG.
    (Comment 12) One comment asked whether followup links to the
original report will be available when submitting the report through
the Web-based system.
    (Response) When the initial ICSR is submitted through the SRP,
users will be able to return to the initial ICSR and submit followup
reports as more information about the reported adverse experience
becomes available. Users may log in to their SRP accounts, locate the
ICSR record, and modify or add to the initial ICSR. Users may submit as
many followup reports as necessary. More detailed information on how to
modify or add to an initial ICSR is available on the SRP Web site.
    Similarly, the eSubmitter tool, which can be used for the
submission of vaccine reports through the ESG into VAERS, allows for
the creation and submission of both initial reports and followup
reports as more information regarding the adverse event becomes
available. Use of the same unique case identification number for the
initial ICSR and any followup reports will be essential to ensure that
the reports are linked in the database.

C. Waivers

    In the proposed rule, we proposed allowing for the submission of
requests for temporary waivers from the electronic format requirement
and stated that waivers would be granted on a time-limited basis for
``good cause'' shown. While noting that the details for submitting
waiver requests would be announced in guidance, we requested comment on
what circumstances would constitute ``good cause'' justifying a waiver
from the electronic submission requirement.
    (Comment 13) One comment requested a categorical exemption from the
electronic reporting requirement for small business entities, which the
comment defined as any business with fewer than 100 employees and less
than $10,000,000 in annual sales. The comment noted difficulties that
these entities had with FDA's system for electronic establishment
registration and drug listing and expressed concern that these
businesses would have similar difficulties with the electronic
submission of safety reports.
    (Response) FDA has concluded that it will not grant a categorical
exemption from the electronic safety reporting requirement for small
business entities. We anticipate that receiving all required
postmarketing safety reports electronically will allow us to more
rapidly review the reports, identify emerging safety problems, and
disseminate safety information. We believe that any categorical
exemption from the electronic submission requirement will significantly
limit these important benefits. As we stated in the preamble to the
proposed rule, we believe a waiver will only be needed in rare
circumstances.
    We appreciate the commenter's concern about potential difficulties
with the electronic submission of safety reports through FDA's system.
We believe that the SRP provides a simple, user-friendly system for
submission of ICSRs into the FAERS database. The SRP is similar to
systems used for online purchases and other Web-based transactions. FDA
has been receiving safety reports through the SRP for the Center for
Food Safety and Applied Nutrition, the Center for Veterinary Medicine,
and the Center for Tobacco Products since 2010. In addition, FDA
intends to provide technical assistance to help resolve any problems.
    We believe that the eSubmitter tool, which may be used for the
electronic submission of ICSRs for vaccines, provides a simple and
straightforward method for submitting these reports. Furthermore,
submission testing is available so that users will have the opportunity
to try out the system before the rule becomes effective.
    FDA has been working with both large and small companies and has
been successfully receiving voluntary electronic submissions of ICSRs
through the ESG since 2001. We believe our experience to date with the
electronic submission of safety reports will help us to minimize
problems with electronic submission that regulated entities may have,
especially entities new to the system. We also believe that the
effective date adopted in this rule will permit the Agency and industry
sufficient time to ensure that the systems are fully functional and
that any technical problems are worked out by the time the requirements
of this rule become effective.
    (Comment 14) One comment recommended allowing a good cause waiver
in cases of natural or manmade disaster. The same comment also
suggested allowing a time-limited waiver for companies bringing their
first commercially available product to market.
    (Response) We agree that natural or manmade disasters may present
situations where a waiver from the electronic submission requirement
would be appropriate. For example, in these situations, electricity may
be unavailable for an extended period of time, and electronic
submission of safety reports would not be feasible. We do not agree
that a time-limited waiver for companies bringing their first
commercially available product to market will be necessary or
appropriate.

We believe the electronic submission systems are easy to use and will
be fully functional by the time this rule becomes effective.
Furthermore, as explained in the previous response, FDA is prepared to
assist companies to ensure that any problems with electronic submission
are resolved.
    (Comment 15) One comment suggested that temporary waivers should be
granted for unplanned, extended-duration ESG downtime; business
continuity or disaster recovery situations where a company's
pharmacovigilance system access may be down for a period of time and
the volume of reports is too high to use the Web-based system requiring
manual entry; or where human resources are greatly diminished, for
example, as a result of pandemic or terror attack.
    (Response) We agree that disaster recovery situations, pandemics,
or terror attacks may present circumstances in which a waiver from the
electronic submission requirement would be appropriate. We believe it
is unlikely that the ESG would experience unplanned downtime of
extended duration such that a waiver from the electronic submission
requirement would be necessary. However, if such a situation were to
occur, a waiver might be appropriate.
    (Comment 16) One comment suggested that the components of a request
for a waiver could include the nature of the inability to comply, the
anticipated time to recover, and a crisis manager contact for the
company who would be accountable to FDA for followup and resolution.
The comment also requested that FDA include in its guidance the type of
documentation that must be kept and the documentation FDA will provide
as a record of the situation for future inspections or audits.
    (Response) We agree with the suggestion that a waiver request
should include the nature of the inability to comply, the anticipated
time to recover, and a company contact. Though additional relevant
information could also be included in a waiver request, the components
suggested for inclusion would allow us to assess the reasonableness of
a waiver request and would ensure that we are able to limit the waiver
to the time necessary. Accordingly, in the postmarketing safety reports
guidance issued today in conjunction with this rule, we have stated
that a waiver request should include the reason for the request and a
proposed end date for the waiver. To follow up with the company, FDA
intends to contact the individual who submitted the request. Although
not addressed in the postmarketing safety reports guidance, we believe
that in the normal course of business, it would be usual and customary
for companies to maintain adequate records of the situation leading to
a waiver request and documentation related to the waiver request.
    (Comment 17) Two comments stated that FDA should provide a
telephone contact for requesting a temporary waiver, because during a
crisis situation, it may be difficult to put together a comprehensive
request. One of the comments also suggested fax as an alternative for
submitting a waiver request.
    (Response) Consistent with the procedures for requesting waivers of
other FDA requirements, requests for waivers of the electronic safety
reporting requirement should be submitted to FDA in writing by mail as
described in the postmarketing safety reports guidance issued today.
The Agency is exploring other methods that may facilitate submission of
waiver requests, and we will update the postmarketing safety reports
guidance, as appropriate, to reflect any changes in waiver request
procedures.

D. ICSR Submissions

1. Content
    (Comment 18) One comment requested clarification on the types of
attachments that are required as part of an ICSR submission.
    (Response) The final rule includes a definition of ``ICSR
attachments'' for clarification, but the rule does not change the types
of attachments that may be necessary as part of an ICSR submission. As
noted previously in this document, in the proposed rule, and in final
Sec. Sec.  310.305(b), 314.80(a), and 600.80(a), examples of ICSR
attachments that may be necessary include published articles that must
accompany ICSRs based on scientific literature (Sec. Sec.  314.80(d)
and 600.80(d)) and other supporting information, such as hospital
discharge summaries and autopsy reports.
    (Comment 19) One comment asked whether the ICSR attachments will be
made public and whether companies will be required to redact the
patient information from the attachments. The comment noted that
requiring the company to redact patient information, such as address
and birth date would create a significant additional burden.
    (Response) FDA will not publicly release names or any other
identifying information about patients contained in ICSR attachments.
FDA redacts patient names and other identifying information before
publicly releasing information contained in postmarketing safety
reports. Persons submitting reports should not redact information
contained in ICSRs or ICSR attachments before submitting them to FDA.
We understand that companies may receive documents from reporters that
are already redacted. Those documents should be submitted to FDA as
received from the reporter and should not be redacted any further.
    (Comment 20) Proposed Sec.  310.305(c)(1)(i) stated that each 15-
day ``Alert report'' must be accompanied by the ``current content of
the labeling'' in electronic format unless it is already on file at
FDA. One comment requested clarification of what ``content of the
labeling'' means, suggesting that it could refer to the entire label or
only certain sections or certain types of information in the labeling.
    (Response) As set forth in Sec.  314.50(l)(1)(i), the ``content of
labeling'' refers to the contents of the package insert or professional
labeling. It is the information required by Sec. Sec.  201.56, 201.57,
and 201.80, in the format specified. For products subject to Sec.
310.305(c)(1)(i), the content of labeling is submitted to FDA in
Structured Product Labeling (SPL) format as part of the electronic drug
listing process. Further information about electronic submission of
content of labeling and SPL format is provided in the guidance for
industry entitled ''Providing Regulatory Submissions in Electronic
Format--Drug Establishment Registration and Drug Listing'' and the
draft guidance ``SPL Standard for Content of Labeling--Technical Qs &
As'' (available on FDA's Web site at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm) which,
when finalized, will represent the Agency's current thinking.
    (Comment 21) Proposed Sec. Sec.  310.305(d)(1)(i), 314.80(f)(1)(i),
and 600.80(f)(1)(i) listed ``patient identification code'' as an
element to be included in each ICSR. Proposed Sec. Sec.  310.305(f),
314.80(i), and 600.80(i), entitled ``Patient privacy,'' stated: ``An
applicant should not include in reports under this section the names
and addresses of individual patients; instead, the applicant should
assign a unique code to each report.'' \15\ One comment requested that
we clarify

whether the term ``patient identification code'' (used in proposed
Sec. Sec.  310.305(d)(1)(i), 314.80(f)(1)(i), and 600.80(f)(1)(i)) and
the term ``unique code for each report'' as used in the provisions
addressing patient privacy (proposed Sec. Sec.  310.305(f), 314.80(i),
and 600.80(i)) are intended to be different codes.
---------------------------------------------------------------------------

    \15\ Both proposed and final Sec.  310.305(f) use the phrase
``manufacturers, packers, and distributors'' in place of the term
``applicant,'' because Sec.  310.305 applies to prescription drugs
for human use without approved NDAs. Proposed Sec.  600.80(i) and
final Sec.  600.80(j) addressing patient privacy state: ``For
nonvaccine biological products, an applicant should not include in
reports . . .''
---------------------------------------------------------------------------

    (Response) The ``patient identification code'' listed as a
reporting element to be included in ICSRs (in Sec. Sec.
310.305(d)(1)(i), 314.80(f)(1)(i), and 600.80(f)(1)(i)) and the
``unique code for each report'' discussed in the provision on patient
privacy (in proposed Sec. Sec.  310.305(f), 314.80(i), and 600.80(i))
are referring to the same code. Entities that submit ICSRs for drug and
nonvaccine biological products should not include names and contact
information for patients in the ICSRs. Rather, a unique code should be
used instead of the patient's name and contact information in the
patient information section of the ICSR.\16\ The intent of using such a
code is to protect the privacy of patients who have experienced adverse
events that are being reported to FDA, while allowing the submitter to
know the patient's identity and contact information for reference
purposes. We agree that as proposed, the requirement is unclear.
Therefore, we are revising the sections entitled ``Patient privacy''
(Sec. Sec.  310.305(f), 314.80(i), and 600.80(j)) to state: ``. . .
should not include in reports under this section the names and
addresses of individual patients; instead, the applicant should assign
a unique code for identification of the patient.'' We believe this
change to the final rule will make clearer that the ``patient
identification code'' included in the list of ICSR reporting elements
(for drug and nonvaccine biological products) and the code described in
the sections on patient privacy are referring to the same code, which
is intended to protect the identity of patients. Section 329.100(d)
also uses the same language.
---------------------------------------------------------------------------

    \16\ The patient's name and contact information should only be
included in an ICSR when the patient is the reporter. Under those
circumstances, the patient-reporter's name and contact information
should be included in the initial reporter section of the ICSR but
not in the patient information section of the ICSR. In the patient
information section of the ICSR, a unique code should be used
instead of the patient-reporter's name and contact information.
---------------------------------------------------------------------------

    We note, however, that Sec. Sec.  310.305(d), 314.80(f),
329.100(b), and 600.80(f) and (g) that set forth the ICSR reporting
elements, as finalized, also require a ``unique case identification
number'' for each ICSR. This unique case identification number is
distinct from the patient identification code. The unique case
identification number, which must be the same in the initial ICSR and
any subsequent followup ICSR(s), was referred to as the Manufacturer
Report Number on Form FDA 3500A and VAERS-1, and it allows FDA to track
an individual case over its life cycle.
    (Comment 22) One comment noted that, in the past, the ESG has
accepted ICSRs for which the applicant does not have all categories of
information. The comment sought to confirm that ICSRs would not be
rejected by the ESG if there are any gaps in categories of information.
    (Response) The ESG will continue to operate as it has and will
accept ICSRs for which the applicant may not have all categories of
information. Even though the ESG and SRP accept ICSRs for which there
are gaps in certain categories of information, it is important for
applicants to include all information about the reported event that is
known to the applicant.
2. Timing of Report Submissions
    (Comment 23) One comment requested confirmation that the ESG will
be available 24 hours a day, 7 days a week, and that ICSRs submitted
outside of business hours will be considered timely (if submitted
within the required time frame). The comment also requested that we
provide guidance on procedures for planned and unplanned downtime of
the ESG and how the downtime affects submission deadlines.
    (Response) FDA intends to make the ESG available 24 hours a day, 7
days a week to receive electronic submissions. Additional information
explaining how submission dates are calculated if the ESG and/or the
FAERS database is temporarily unavailable is provided in the
postmarketing safety reports guidance issued today. We note that FDA
also intends to make the SRP available 24 hours a day, 7 days a week to
receive submissions.

E. International Harmonization

    (Comment 24) One comment suggested that we reference the ICH
Harmonized Tripartite Guideline instead of listing, in the rule,
categories of information to be included in ICSRs.
    (Response) We set forth the categories of information to be
included in ICSRs because we believe that this is a clear and concise
way to communicate the information to be included when reporting
adverse events to FDA and to move away from reliance on paper forms. We
considered the ICH guidelines when creating these categories and
believe that the categories included are either consistent with
international standards or can be accommodated as local requirements
using international transmission standards.
    (Comment 25) One comment asked what version of the ICH E2B standard
(i.e., the ICH guideline on data elements for transmission of ICSRs)
will be accepted.
    (Response) It has been FDA's practice to accept both the latest
version of the ICH E2B standard in addition to the previous version.
This practice has allowed applicants reasonable time to transition to
the updated ICH E2B standard. Any changes to submission standards will
be provided in guidance, as appropriate.\17\
---------------------------------------------------------------------------

    \17\ Further information about E2B message standards accepted by
FAERS is available on the FAERS Electronic Submissions Web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm115894.htm.
---------------------------------------------------------------------------

    (Comment 26) One comment noted that the EU Drug Regulatory
Authorities Pharmacovigilance system (EudraVigilance) has different
validators than FDA's reporting system. As a result, some ICSRs would
be accepted by FDA that would not be accepted by the European Medicines
Agency. The comment requested that if new validators are placed on the
ESG they be aligned with the EudraVigilance validators so that both
systems accept the same reports.
    (Response) It would not be functionally workable or practical to
commit, in advance, to incorporating changes made by other regulatory
bodies to ensure complete consistency among the reporting systems. FDA
will continue to work with international standards organizations when
developing new technical specifications so that differences in those
specifications are kept to a minimum.

F. Technical Specifications

    The proposed rule indicated that standards and technical
specifications will be addressed in guidance documents rather than set
forth in the final rule.
    (Comment 27) One comment noted that changes to technical standards
or specifications can increase costs to companies. The comment
expressed concern that by adopting changes in guidance documents, the
changes can occur more quickly and more frequently, resulting in a
greater burden to companies. The comment stated that it is important
that required technical standards or specifications not be changed
frequently and that when they

are changed, adequate time be allowed for public comment.
    (Response) We understand the concern that frequent changes in
technical standards and specifications may increase the cost of
compliance to companies. FDA does not anticipate frequent changes.
However, it is important for FDA to retain flexibility so that we can
be responsive to the rapidly changing technological environment. We
believe that the use of guidance documents to communicate technical
specifications will benefit both companies and the Agency. If FDA were
to set forth technical specifications in regulations, the result could
be that companies would be bound to standards and specifications that
are outdated. Maintaining older systems can also be a resource burden
to companies.

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, 745A, 760, and 801 of
the FD&C Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356, 356a,
356b, 356c, 360, 371, 374, 375, 379k-1, 379aa, and 381); and the PHS
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 final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct 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). FDA believes that this final rule is not a significant
regulatory action as defined by Executive Order 12866.
    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 few safety
reports and the Agency's Web-based system for submitting reports
electronically will require little additional cost per report, the
Agency believes that this final rule will not have a significant
economic impact on a substantial number of small entities.
    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 $141 million, using the most current (2013) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.
    The final rule requires the submission of all postmarketing safety
reports, including periodic reports, to FDA in an electronic format. In
addition, manufacturers of products distributed under a biologic
license are required to submit lot distribution reports electronically.
The public health benefits of this final rule, quicker access to
postmarketing safety information, were not quantified. The final rule
will generate an annual savings for the Agency of about $0.8 million,
which is primarily a savings in the cost of processing paper. Total
one-time costs to industry will be between $5.9 million to $7.5
million; the costs are for changing standard operating procedures
(SOPs) and for training personnel. Annualized over 10 years at a 7
percent discount rate, the costs are from $0.8 million to $1.1 million.
At a 3 percent discount rate over 10 years, the annualized costs are
$0.7 million to $0.9 million.
    The full assessment of economic impacts is available in Docket No.
FDA-2008-N-0334 and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 1).

VII. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions 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). The title,
description, and respondent description of the information collection
provisions are shown below 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 each
collection of information.
    Title: Postmarketing Safety Reports for Human Drug and Biological
Products: Electronic Submission Requirements.
    Description: The final rule amends FDA's postmarketing safety
reporting regulations for human drug and biological products under
parts 310, 314, and 600, and adds part 329, 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 submit postmarketing safety reports to the
Agency. Section 760 of the FD&C 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 serious adverse events associated with their products. Under
Sec.  600.81, applicants with approved BLAs must submit biological lot
distribution reports to the Agency. In this rule, FDA is requiring that
these postmarketing reports be submitted to the Agency in an electronic
format that FDA can process, review, and archive. The final rule also
states that FDA will 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 requires that they be
submitted in an electronic format. Under Sec. Sec.  310.305(e)(2),
314.80(g)(2), 329.100(c)(2), 600.80(h)(2), and 600.81(b)(2), we are
also permitting those subject to mandatory reporting requirements 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 FDA 3500A) and 0910-0230. The information
collection for part 600 is approved under OMB control numbers 0910-0291
(Form 3500A) and 0910-0308. The burdens currently estimated

under parts 310, 314, and 600, for submission of postmarketing safety
reports to FDA for human drugs and biological products, do not change
as a result of this final 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 final rule, including obtaining an electronic certificate,
revising SOPs, and becoming familiar 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 Sec.  600.81.
    OMB has approved the burden associated with submissions required by
section 760 of the FD&C Act under OMB control number 0910-0636.
    In table 1 of this document, we have estimated the burdens
associated with the submission of waivers, under Sec. Sec.
310.305(e)(2), 314.80(g)(2), 329.100(c)(2), 600.80(h)(2), and
600.81(b)(2). We expect few waiver requests (see section II.C). We
estimate that approximately one manufacturer will request a waiver
annually under Sec. Sec.  310.305(e)(2), 329.100(c)(2), and
600.81(b)(2), and five manufacturers will request a waiver annually
under Sec. Sec.  314.80(g)(2) and 600.80(h)(2). We estimate that each
waiver request will take approximately 1 hour to prepare and submit to
us.
    Description of Respondents: Manufacturers, packers, and
distributors of marketed prescription drug products that are not the
subject of approved applications, applicants with approved NDAs, ANDAs,
and BLAs, and those that market nonprescription drugs for human use
without an approved application.
    Burden Estimate: Table 1 of this document provides an estimate of
the new annual reporting burden for submitting requests under the
waiver requirement in this final rule.

                                   Table 1--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
                                                     Number of
         21 CFR Sections             Number of     responses per   Total annual      Hours per      Total hours
                                    respondents     respondent       responses       response
----------------------------------------------------------------------------------------------------------------
                                   Waivers--Electronic Format for Submissions
----------------------------------------------------------------------------------------------------------------
310.305(e)(2)...................               1               1               1               1               1
314.80(g)(2)....................               5               1               5               1               5
329.100(c)(2)...................               1               1               1               1               1
600.80(h)(2)....................               5               1               5               1               5
600.81(b)(2)....................               1               1               1               1               1
                                 -------------------------------------------------------------------------------
    Total Reporting Burden......  ..............  ..............  ..............  ..............              13
----------------------------------------------------------------------------------------------------------------

A. Reporting Costs

    Based on the average hourly wage ($79) as calculated in section VI
(Analysis of Impacts) of the final rule, the cost to respondents would
be $1,027 (13 x $79).
    Tables 2 through 5 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 2--OMB Control Number 0910-0291 ``MedWatch: The FDA Medical Products Reporting Program''
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Number of
                          21 CFR Sections                               Number of      responses per     Total annual      Hours per       Total hours
                                                                       respondents       respondent       responses         response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Form FDA 3500A (MedWatch: The FDA Safety Information and Adverse                600              683          409,608              1.1          450,568
 Event Reporting Program--Mandatory) (Sec.  Sec.   310.305--Records
 and reports concerning adverse drug experiences on marketed
 prescription drugs for human use without approved new drug
 applications, 314.80--Postmarketing reporting of adverse drug
 experiences, 314.98--Postmarketing reports, and 600.80--
 Postmarketing reporting of adverse experiences)...................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Based on the average hourly wage ($79) as calculated in section VI
(Analysis of Impacts) of the proposed rule, the cost to respondents
would be $39,895,948 (505,012 x $79).

                   Table 3--OMB Control Number 0910-0230 ``Adverse Drug Experience Reporting''
----------------------------------------------------------------------------------------------------------------
                                                     Number of
         21 CFR Sections             Number of     responses per   Total annual      Hours per      Total hours
                                    respondents     respondent       responses       response
----------------------------------------------------------------------------------------------------------------
310.305(c)(5)--Reporting                       1            1                  1               1               1
 requirements...................
314.80(c)(2)--Periodic adverse               642           17.88          11,478              60         688,680
 drug experience reports........
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............         688,681
----------------------------------------------------------------------------------------------------------------

    Based on the average hourly wage ($79) as calculated in section VI
of the proposed rule, the cost to respondents would be $54,405,799
(688,681 x $79).

    Table 4--OMB Control Number 0910-0308 ``Adverse Experience Reporting for Licensed Biological Product; and
                                                General Records''
----------------------------------------------------------------------------------------------------------------
                                                     Number of
         21 CFR Sections             Number of     responses per   Total annual      Hours per      Total hours
                                    respondents     respondent       responses       response
----------------------------------------------------------------------------------------------------------------
600.80(c)(1)--Postmarketing 15-              108          801.69          86,583               1          86,583
 day ``Alert reports'' and
 600.80(e)--Postmarketing
 studies........................
600.80(c)(2)--Periodic adverse               108          530.55          57,300              28       1,604,400
 experience reports.............
600.81--Distribution Reports....             108            3.23             349               1             349
600.90--Waivers.................              21            1                 21               1              21
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............       1,691,353
----------------------------------------------------------------------------------------------------------------

    Based on the average hourly wage ($79) as calculated in section VI
of the proposed rule, the cost to respondents would be $133,616,887
(1,691,353 x $79).

 Table 5--OMB Control Number 0910-0636 ``Guide for Industry on Labeling of Nonprescription Human Drug Products Marketed Without an Approved Application
                                as Required by the Dietary Supplement and Nonprescription Drug Consumer Protection Act''
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Number of
                                                                        Number of      responses per     Total annual      Hours per       Total hours
                                                                       respondents       respondent       responses         response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Reports of serious adverse drug events under section 760 of the                  50              250           12,500                2           25,000
 FD&C Act (21 U.S.C. 379aa((b) and (c))............................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Based on the average hourly wage ($79) as calculated in section VI
of the proposed rule, the cost to respondents would be $1,975,000
(25,000 x $79).

B. Capital Costs

    As explained in section VI (Analysis of Impacts), total one-time
costs to industry would be between $5.9 million to $7.5 million; the
costs are for changing standard SOPs and training personnel. Annualized
over 10 years at a 7 percent discount rate, the costs will be from 0.8
million to $1.1 million. At a 3 percent discount rate over 10 years,
the annualized costs are $0.7 million to $0.9 million.
    The information collection provisions of this final rule have been
submitted to OMB for review. Prior to the effective date of this final
rule, FDA will publish a notice in the Federal Register announcing
OMB's decision to approve, modify, or disapprove the information
collection provisions in this final rule. An Agency may not conduct or
sponsor, and a person is not required to respond to, a collection of
information unless it displays a currently valid OMB control number.

VIII. Federalism

    FDA has analyzed this final 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. Reference

    The following reference has been placed on display in the Division
of Dockets Management (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852 and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday,
and is available electronically at http://www.regulations.gov.

    1. Regulatory Impact Analysis, Regulatory Flexibility Analysis,
and Unfunded Mandates Reform Act Analysis for Postmarketing Safety
Reports for Human Drug and Biological Products; Electronic
Submission Requirements; Final Rule, available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

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 329

    Administrative practice and procedure, Over-the-counter 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, 21 CFR parts 310, 314, and 600 are
amended and a new part 329 is added as follows:

PART 310--NEW DRUGS

0
1. The authority citation for 21 CFR part 310 is revised to read as
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 361(a), 371, 374, 375, 379e, 379k-1; 42 U.S.C. 216, 241,
242(a), 262, 263b-263n.

0
2. Section 310.305 is amended by:
0
a. Removing the word ``shall'' each time it appears and by adding in
its place the word ``must'';
0
b. Adding alphabetically in paragraph (b) the definitions of
``Individual case safety report (ICSR)'' and ``ICSR attachments'';
0
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);
0
d. Revising paragraph (d); and
0
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) removing ``(c)(4)'' and
adding 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.
    ICSR attachments. Documents related to the adverse drug experience
described in an ICSR, such as medical records, hospital discharge
summaries, or other documentation.
* * * * *
    (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 ICSR 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 as an ICSR attachment
unless it is already on file at FDA.
* * * * *
    (3) Submission of reports. * * * 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 ICSR submission;
    (iv) Description of adverse drug experience (including a concise
medical narrative);
    (v) Adverse drug experience term(s);
    (vi) Description of relevant tests, including dates and laboratory
data; and
    (vii) Other relevant patient history, including preexisting medical
conditions.
    (3) Suspect medical product(s).
    (i) Name;
    (ii) Dose, frequency, and route of administration used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) Whether the product is a combination product as defined in
Sec.  3.2(e) of this chapter;
    (vi) Whether the product is a prescription or nonprescription
product;
    (vii) Whether adverse drug experience abated after drug use stopped
or dose reduced;
    (viii) Whether adverse drug experience reappeared after
reintroduction of drug;
    (ix) Lot number;
    (x) Expiration date;
    (xi) National Drug Code (NDC) number; and
    (xii) Concomitant medical products and therapy dates.
    (4) Initial reporter information.
    (i) Name, address, and telephone number;
    (ii) Whether the initial reporter is a health care professional;
and
    (iii) Occupation, if a health care professional.
    (5) Manufacturer, packer, or distributor information.
    (i) Manufacturer, packer, or distributor name and contact office
address;
    (ii) Telephone number;
    (iii) Report source, such as spontaneous, literature, or study;
    (iv) Date the report was received by manufacturer, packer, or
distributor;
    (v) Whether the ICSR is a 15-day ``Alert report'';
    (vi) Whether the ICSR is an initial report or followup report; and
    (vii) Unique case identification number, which must be the same in
the initial report and any subsequent followup report(s).
    (e) Electronic format for submissions. (1) Each report required to
be submitted to FDA under this section, including the ICSR and any ICSR
attachments, must be submitted in an electronic format that FDA can
process, review, and archive. FDA will issue guidance on how to provide
the electronic submission (e.g., method of transmission, media, file
formats, preparation and organization of files).
    (2) Each person identified in paragraph (c)(1)(i) of this section
may request, in writing, a temporary waiver of the requirements in
paragraph (e)(1)

of this section. These waivers will be granted on a limited basis for
good cause shown. FDA will issue guidance on requesting a waiver of the
requirements in paragraph (e)(1) of this section.
    (f) Patient privacy. Manufacturers, packers, and distributors
should not include in reports under this section the names and
addresses of individual patients; instead, the manufacturer, packer,
and distributor should assign a unique code for identification of the
patient. The manufacturer, packer, and distributor should include the
name of the reporter from whom the information was received as part of
the initial reporter information, even when the reporter is the
patient. The names of patients, individual reporters, health care
professionals, hospitals, and geographical identifiers in adverse drug
experience reports are not releasable to the public under FDA's public
information regulations in part 20 of this chapter.
* * * * *

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
3. The authority citation for 21 CFR part 314 is revised to read as
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a,
356b, 356c, 371, 374, 379e, 379k-1.

0
4. Section 314.80 is amended:
0
a. By removing the word ``shall'' each time it appears and by adding in
its place the word ``must'';
0
b. In paragraph (a) by alphabetically adding the definitions for
``Individual case safety report (ICSR)'' and ``ICSR attachments'';
0
c. In paragraph (c)(1)(i) by removing the phrase ``in no case later
than 15 calendar days of'' and by adding in its place the phrase ``no
later than 15 calendar days from'';
0
d. By removing the last sentence of paragraph (c)(1)(ii);
0
e. By removing paragraph (c)(1)(iv);
0
f. By revising paragraph (c) introductory text, the first and third
sentences of paragraph (c)(1)(iii) introductory text, and paragraph
(c)(2)(ii);
0
g. By removing paragraph (d)(2) and by redesignating paragraph (d)(1)
as paragraph (d) and revising the first sentence of newly redesignated
paragraph (d);
0
h. By removing paragraph (e)(2) and by redesignating paragraph (e)(1)
as paragraph (e);
0
i. By revising paragraph (f);
0
j. By redesignating paragraph (g) through paragraph (k) as paragraph
(h) through paragraph (l); and by revising newly redesignated paragraph
(i); and
0
k. By adding new paragraph (g) to read as follows:

Sec.  314.80  Postmarketing reporting of adverse drug experiences.

    (a) * * *
    Individual case safety report (ICSR). A description of an adverse
drug experience related to an individual patient or subject.
    ICSR attachments. Documents related to the adverse drug experience
described in an ICSR, such as medical records, hospital discharge
summaries, or other documentation.
* * * * *
    (c) Reporting requirements. The applicant must submit to FDA
adverse drug experience information as described in this section.
Except as provided in paragraph (g)(2) of this section, these reports
must be submitted to the Agency in electronic format as described in
paragraph (g)(1) of this section.
    (1) * * *
    (iii) Submission of reports. The requirements of paragraphs
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of
postmarketing 15-day Alert reports, also apply to any person other than
the applicant whose name appears on the label of an approved drug
product as a manufacturer, packer, or distributor (nonapplicant). * * *
If a nonapplicant elects to submit adverse drug experience reports to
the applicant rather than to FDA, the nonapplicant must submit, by any
appropriate means, each report to the applicant within 5 calendar days
of initial receipt of the information by the nonapplicant, and the
applicant must then comply with the requirements of this section. * * *
* * * * *
    (2) * * *
    (ii) Each periodic report is required to contain:
    (A) Descriptive information. (1) A narrative summary and analysis
of the information in the report;
    (2) An analysis of the 15-day Alert reports submitted during the
reporting interval (all 15-day Alert reports being appropriately
referenced by the applicant's patient identification code, adverse
reaction term(s), and date of submission to FDA);
    (3) A history of actions taken since the last report because of
adverse drug experiences (for example, labeling changes or studies
initiated); and
    (4) An index consisting of a line listing of the applicant's
patient identification code, and adverse reaction term(s) for all ICSRs
submitted under paragraph (c)(2)(ii)(B) of this section.
    (B) ICSRs for serious, expected, and nonserious adverse drug
experiences. An ICSR for each adverse drug experience not reported
under paragraph (c)(1)(i) of this section (all serious, expected and
nonserious adverse drug experiences). All such ICSRs must be submitted
to FDA (either individually or in one or more batches) within the
timeframe specified in paragraph (c)(2)(i) of this section. ICSRs must
only be submitted to FDA once.
* * * * *
    (d) Scientific literature. A 15-day Alert report based on
information in the scientific literature must be accompanied by a copy
of the published article. * * *
* * * * *
    (f) 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 ICSR submission;
    (iv) Description of adverse drug experience (including a concise
medical narrative);
    (v) Adverse drug experience term(s);
    (vi) Description of relevant tests, including dates and laboratory
data; and
    (vii) Other relevant patient history, including preexisting medical
conditions.
    (3) Suspect medical product(s).
    (i) Name;
    (ii) Dose, frequency, and route of administration used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) Whether the product is a prescription or nonprescription
product;
    (vi) Whether the product is a combination product as defined in
Sec.  3.2(e) of this chapter;
    (vii) Whether adverse drug experience abated after drug use stopped
or dose reduced;
    (viii) Whether adverse drug experience reappeared after
reintroduction of drug;
    (ix) Lot number;
    (x) Expiration date;
    (xi) National Drug Code (NDC) number; and
    (xii) Concomitant medical products and therapy dates.
    (4) Initial reporter information.

    (i) Name, address, and telephone number;
    (ii) Whether the initial reporter is a health care professional;
and
    (iii) Occupation, if a health care professional.
    (5) Applicant information.
    (i) Applicant name and contact office address;
    (ii) Telephone number;
    (iii) Report source, such as spontaneous, literature, or study;
    (iv) Date the report was received by applicant;
    (v) Application number and type;
    (vi) Whether the ICSR is a 15-day ``Alert report'';
    (vii) Whether the ICSR is an initial report or followup report; and
    (viii) Unique case identification number, which must be the same in
the initial report and any subsequent followup report(s).
    (g) Electronic format for submissions. (1) Safety report
submissions, including ICSRs, ICSR attachments, and the descriptive
information in periodic reports, must be in an electronic format that
FDA can process, review, and archive. FDA will issue guidance on how to
provide the electronic submission (e.g., method of transmission, media,
file formats, preparation and organization of files).
    (2) An applicant or nonapplicant may request, in writing, a
temporary waiver of the requirements in paragraph (g)(1) of this
section. These waivers will be granted on a limited basis for good
cause shown. FDA will issue guidance on requesting a waiver of the
requirements in paragraph (g)(1) of this section.
* * * * *
    (i) Patient privacy. An applicant should not include in reports
under this section the names and addresses of individual patients;
instead, the applicant should assign a unique code for identification
of the patient. The applicant should include the name of the reporter
from whom the information was received as part of the initial reporter
information, even when the reporter is the patient. The names of
patients, health care professionals, hospitals, and geographical
identifiers in adverse drug experience reports are not releasable to
the public under FDA's public information regulations in part 20 of
this chapter.
* * * * *

0
5. Section 314.98 is revised to read as follows:

Sec.  314.98  Postmarketing reports.

    (a) Each applicant having an approved abbreviated new drug
application under Sec.  314.94 that is effective must comply with the
requirements of Sec.  314.80 regarding the reporting and recordkeeping
of adverse drug experiences.
    (b) Each applicant must make the reports required under Sec.
314.81 and section 505(k) of the Federal Food, Drug, and Cosmetic Act
for each of its approved abbreviated applications.

0
6. Part 329 is added to read as follows:

PART 329--NONPRESCRIPTION HUMAN DRUG PRODUCTS SUBJECT TO SECTION
760 OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371, 379aa.

Sec.  329.100  Postmarketing reporting of adverse drug events under
section 760 of the Federal Food, Drug, and Cosmetic Act.

    (a) Reporting requirements. Reports of serious adverse events
required by section 760 of the Federal Food, Drug, and Cosmetic Act
(FD&C Act) must include the information specified in this section, as
applicable. Except as provided in paragraph (c)(2) of this section,
these reports must be submitted to the Agency in electronic format as
described in paragraph (c)(1) of this section.
    (b) Contents of reports. For purposes of reporting serious adverse
events under section 760 of the FD&C Act, an individual case safety
report (ICSR) constitutes the MedWatch form required to be submitted by
section 760(d) of the FD&C Act. 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 event.
    (i) Outcome attributed to adverse drug event;
    (ii) Date of adverse drug event;
    (iii) Date of ICSR submission;
    (iv) Description of adverse drug event (including a concise medical
narrative);
    (v) Adverse drug event term(s);
    (vi) Description of relevant tests, including dates and laboratory
data; and
    (vii) Other relevant patient history, including preexisting medical
conditions.
    (3) Suspect medical product(s).
    (i) Name;
    (ii) Dose, frequency, and route of administration used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) Whether the product is a combination product as defined in
Sec.  3.2(e) of this chapter;
    (vi) Whether the product is a prescription or nonprescription
product;
    (vii) Whether adverse drug event abated after drug use stopped or
dose reduced;
    (viii) Whether adverse drug event reappeared after reintroduction
of drug;
    (ix) Lot number;
    (x) Expiration date;
    (xi) National Drug Code (NDC) number; and
    (xii) Concomitant medical products and therapy dates.
    (4) Initial reporter information.
    (i) Name, address, and telephone number;
    (ii) Whether the initial reporter is a health care professional;
and
    (iii) Occupation, if a health care professional.
    (5) Responsible person (as defined in section 760(b) of the FD&C
Act) information.
    (i) Name and contact office address;
    (ii) Telephone number;
    (iii) Report source, such as spontaneous;
    (iv) Date the report was received by responsible person;
    (v) Whether the ICSR is a 15-day report;
    (vi) Whether the ICSR is an initial report or followup report; and