Document ID: FDA-2008-N-0334-0009
Agency: fda
Document Type: Rule
Title: Postmarketing Safety Reports for Human Drug and Biological Products;
Electronic Submission Requirements
Posted Date: 2014-06-10T04:00Z

[Federal Register Volume 79, Number 111 (Tuesday, June 10, 2014)]
[Rules and Regulations]
[Pages 33072-33092]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[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, 240-402-7911.
    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, 301-827-6210.

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

[[Page 33073]]

    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

[[Page 33074]]

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

[[Page 33075]]

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

[[Page 33076]]

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

[[Page 33077]]

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

[[Page 33078]]

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.

[[Page 33079]]

    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

[[Page 33080]]

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 faersesub@fda.hhs.gov 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 
esgprep@fda.hhs.gov.
    (Comment 9) One comment suggested that companies should be able to 
use both the Web-based portal and the ESG

[[Page 33081]]

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.

[[Page 33082]]

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

[[Page 33083]]

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

[[Page 33084]]

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

[[Page 33085]]

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).

[[Page 33086]]

                   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.

[[Page 33087]]

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)

[[Page 33088]]

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.

[[Page 33089]]

    (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
    (vii) Unique case identification number, which must be the same in 
the initial report and any subsequent followup report(s).
    (c) Electronic format for submissions. (1) Each report required to 
be submitted to FDA under section 760 of the FD&C Act, accompanied by a 
copy of the label on or within the retail package of the drug and any 
other documentation (as ICSR attachments), 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) The responsible person may request, in writing, a temporary 
waiver of the requirements in paragraph (c)(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 (c)(1) of this section.
    (d) Patient privacy. The responsible person should not include in 
reports under this section the names and addresses of individual 
patients; instead, the responsible person should assign a unique code 
for identification of the patient. The responsible person should 
include the name of the reporter from whom the information was received 
as part of the initial reporter

[[Page 33090]]

information, even when the reporter is the patient. The names of 
patients, health care professionals, hospitals, and geographical 
identifiers in adverse drug event reports are not releasable to the 
public under FDA's public information regulations in part 20 of this 
chapter.

PART 600--BIOLOGICAL PRODUCTS: GENERAL

0
7. The authority citation for 21 CFR part 600 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 
374, 379k-1; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

Sec.  600.2  [Amended]

0
8. Section 600.2 is amended:
0
a. In paragraph (a) by removing the phrase ``paragraphs (c) or (d)'' 
and adding in its place ``paragraph (c)'', and by removing the phrase 
``adverse experience reports'';
0
b. In paragraph (b) introductory text by removing the phrase 
``paragraphs (b)(1), (b)(2), (b)(3), or (c)'' and adding in its place 
``paragraphs (b)(1), (b)(2), or (c) ``
0
c. By removing paragraph (b)(2) and redesignating paragraph (b)(3) as 
paragraph (b)(2);
0
d. By removing paragraph (d) and redesignating paragraphs (e) and (f) 
as paragraphs (d) and (e).
0
e. In newly redesignated paragraph (e) by removing the Web address 
``http://www.fda.gov/cber/pubinquire.htm'' and adding in its place 
``http://www.fda.gov/BiologicsBloodVaccines/default.htm'' and by 
removing the Web address ``http://www.fda.gov/cder/biologics/default.htm'' and adding in its place ``http://www.fda.gov/Drugs/default.htm''.

0
9. Section 600.80 is amended:
0
a. By removing the word ``shall'' each time it appears and by adding in 
its place the word ``must'';
0
b. By removing the phrase ``licensed manufacturer'' or ``licensed 
manufacturers'' each time it appears and by adding in its place the 
word ``applicant'' or ``applicants'' respectively;
0
c. By removing the phrase ``Licensed manufacturer'' or ``Licensed 
manufacturers'' each time it appears and by adding in its place the 
word ``Applicant'' or ``Applicants'' respectively;
0
d. In paragraph (a) by alphabetically adding the definitions for 
``Individual case safety report (ICSR)'' and ``ICSR attachments'';
0
e. 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
f. In paragraph (c)(1)(ii) by removing the last sentence;
0
g. By removing paragraph (c)(1)(iv);
0
h. By revising paragraph (c) introductory text, the first and third 
sentences of paragraph (c)(1)(iii) introductory text, and paragraph 
(c)(2)(ii);
0
i. By removing paragraph (d)(2) and by redesignating paragraph (d)(1) 
as paragraph (d) and revising the first sentence of paragraph (d);
0
j. By removing paragraph (e)(2) and by redesignating paragraph (e)(1) 
as paragraph (e);
0
k. By revising paragraph (f);
0
l. By redesignating paragraph (g) through paragraph (l) as paragraph 
(i) through paragraph (n) and by revising newly redesignated paragraph 
(j); and
0
m. By adding new paragraphs (g) and (h) to read as follows:

Sec.  600.80  Postmarketing reporting of adverse experiences.

    (a) * * *
    Individual case safety report (ICSR). A description of an adverse 
experience related to an individual patient or subject.
    ICSR attachments. Documents related to the adverse experience 
described in an ICSR, such as medical records, hospital discharge 
summaries, or other documentation.
* * * * *
    (c) Reporting requirements. The applicant must submit to FDA 
postmarketing 15-day Alert reports and periodic safety reports 
pertaining to its biological product as described in this section. 
These reports must be submitted to the Agency in electronic format as 
described in paragraph (h)(1) of this section, except as provided in 
paragraph (h)(2) 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 whose name 
appears on the label of a licensed biological product as a 
manufacturer, packer, distributor, shared manufacturer, joint 
manufacturer, or any other participant involved in divided 
manufacturing. * * * If a person elects to submit adverse experience 
reports to the applicant rather than to FDA, the person must submit, by 
any appropriate means, each report to the applicant within 5 calendar 
days of initial receipt of the information by the person, 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 for 
nonvaccine biological product reports or by the unique case 
identification number for vaccine reports, adverse reaction term(s), 
and date of submission to FDA);
    (3) A history of actions taken since the last report because of 
adverse experiences (for example, labeling changes or studies 
initiated);
    (4) An index consisting of a line listing of the applicant's 
patient identification code for nonvaccine biological product reports 
or by the unique case identification number for vaccine reports and 
adverse reaction term(s) for ICSRs submitted under paragraph 
(c)(2)(ii)(B) of this section; and
    (B) ICSRs for serious, expected and, nonserious adverse 
experiences. An ICSR for each adverse experience not reported under 
paragraph (c)(1)(i) of this section (all serious, expected and 
nonserious adverse 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 for nonvaccine biological 
products. ICSRs for nonvaccine biological products include the 
following information:
    (1) Patient information.
    (i) Patient identification code;
    (ii) Patient age at the time of adverse experience, or date of 
birth;
    (iii) Patient gender; and
    (iv) Patient weight.
    (2) Adverse experience.
    (i) Outcome attributed to adverse experience;
    (ii) Date of adverse experience;
    (iii) Date of report;
    (iv) Description of adverse experience (including a concise medical 
narrative);
    (v) Adverse experience term(s);
    (vi) Description of relevant tests, including dates and laboratory 
data; and

[[Page 33091]]

    (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 experience abated after product use stopped 
or dose reduced;
    (viii) Whether adverse experience reappeared after reintroduction 
of the product;
    (ix) Lot number;
    (x) Expiration date;
    (xi) National Drug Code (NDC) number, or other unique identifier; 
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) Information reported on ICSRs for vaccine products. ICSRs for 
vaccine products include the following information:
    (1) Patient information.
    (i) Patient name, address, telephone number;
    (ii) Patient age at the time of vaccination, or date of birth;
    (iii) Patient gender; and
    (iv) Patient birth weight for children under age 5.
    (2) Adverse experience.
    (i) Outcome attributed to adverse experience;
    (ii) Date and time of adverse experience;
    (iii) Date of report;
    (iv) Description of adverse experience (including a concise medical 
narrative);
    (v) Adverse experience term(s);
    (vi) Illness at the time of vaccination;
    (vii) Description of relevant tests, including dates and laboratory 
data; and
    (viii) Other relevant patient history, including preexisting 
medical conditions.
    (3) Suspect medical product(s), including vaccines administered on 
the same date.
    (i) Name;
    (ii) Dose, frequency, and route or site of administration used;
    (iii) Number of previous vaccine doses;
    (iv) Vaccination date(s) and time(s);
    (v) Diagnosis for use (indication);
    (vi) Whether the product is a combination product (as defined in 
Sec.  3.2(e) of this chapter);
    (vii) Whether the adverse experience abated after product use 
stopped or dose reduced;
    (viii) Whether the adverse experience reappeared after 
reintroduction of the product;
    (ix) Lot number;
    (x) Expiration date;
    (xi) National Drug Code (NDC) number, or other unique identifier; 
and
    (xii) Concomitant medical products and therapy dates.
    (4) Vaccine(s) administered in the 4 weeks prior to the vaccination 
date.
    (i) Name of vaccine;
    (ii) Manufacturer;
    (iii) Lot number;
    (iv) Route or site of administration;
    (v) Date given; and
    (vi) Number of previous doses.
    (5) 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.
    (6) Facility and personnel where vaccine was administered.
    (i) Name of person who administered vaccine;
    (ii) Name of responsible physician at facility where vaccine was 
administered; and
    (iii) Name, address (including city, county, and state), and 
telephone number of facility where vaccine was administered.
    (7) Applicant information.
    (i) Applicant name and contact office address;
    (ii) Telephone number;
    (iii) Report source, such as spontaneous, literature, or study;
    (iv) Date 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).
    (h) 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) Persons subject to the requirements of paragraph (c) of this 
section may request, in writing, a temporary waiver of the requirements 
in paragraph (h)(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 (h)(1) of this 
section. Requests for waivers must be submitted in accordance with 
Sec.  600.90.
* * * * *
    (j) Patient privacy. For nonvaccine biological products, 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 
experience reports are not releasable to the public under FDA's public 
information regulations in part 20 of this chapter. For vaccine adverse 
experience reports, these data will become part of the CDC Privacy Act 
System 09-20-0136, ``Epidemiologic Studies and Surveillance of Disease 
Problems.'' Information identifying the person who received the vaccine 
or that person's legal representative will not be made available to the 
public, but may be available to the vaccinee or legal representative.
* * * * *

0
10. Section Sec.  600.81 is amended:
0
a. By removing the phrase ``licensed manufacturer'' each time it 
appears and by adding in its place the word ``applicant'';
0
b. By removing the word ``shall'' each time it appears and by adding in 
its place the word ``must'';
0
c. By designating the existing text as paragraph (a) and by adding a 
heading for newly designated paragraph (a);

[[Page 33092]]

0
d. In newly designated paragraph (a), by removing from the first 
sentence the phrase ``(see mailing addresses in Sec.  600.2)''; and
0
e. By adding new paragraph (b) to read as follows:

Sec.  600.81  Distribution reports.

    (a) Reporting requirements. * * *
    (b)(1) Electronic format. Except as provided for in paragraph 
(b)(2) of this section, the distribution reports required under 
paragraph (a) of this section must be submitted to the Agency 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) Waivers. An applicant may request, in writing, a temporary 
waiver of the requirements in paragraph (b)(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 (b)(1) of this section. Requests for waivers must be 
submitted in accordance with Sec.  600.90.

Sec.  600.90  [Amended]

0
11. Section 600.90 is amended by removing the phrase ``licensed 
manufacturer'' or ``licensed manufacturer's'' each time it appears and 
by adding in its place the word ``applicant'' or ``applicant's'' 
respectively.

    Dated: June 4, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-13480 Filed 6-9-14; 8:45 am]
BILLING CODE 4160-01-P