[Federal Register Volume 74, Number 161 (Friday, August 21, 2009)]
[Proposed Rules]
[Pages 42184-42203]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-19682]


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Proposed Rules
                                                Federal Register
________________________________________________________________________

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

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Federal Register / Vol. 74, No. 161 / Friday, August 21, 2009 / 
Proposed Rules

[[Page 42184]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 314, and 600

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


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

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

ADDRESSES:  You may submit comments, identified by Docket No. FDA-2008-
N-0334 and/or RIN number 0910-AF96, by any of the following methods, 
except that comments on information collection issues under the 
Paperwork Reduction Act of 1995 must be submitted to the Office of 
Regulatory Affairs, Office of Management and Budget (OMB) (see the 
``Paperwork Reduction Act of 1995'' section of this document).
Electronic Submissions
    Submit electronic comments in the following way:
    <bullet> Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
Written Submissions
    Submit written submissions in the following ways:
    <bullet> FAX: 301-827-6870.
    <bullet> Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal, as described previously, in the ADDRESSES portion 
of this document under Electronic Submissions.
    Instructions: All submissions received must include the agency name 
and Docket No. and Regulatory Information Number (RIN) for this 
rulemaking. All comments received may be posted without change to 
http://www.regulations.gov, including any personal information 
provided. For additional information on submitting comments, see the 
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number(s), found in brackets in the heading of this document, 
into the ``Search'' box and follow the prompts and/or go to the 
Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852.
    The information collection provisions of this proposed rule have 
been submitted to OMB for review. Interested persons are requested to 
fax comments regarding information collection by September 21, 2009, to 
the Office of Information and Regulatory Affairs, OMB. To ensure that 
comments on information collection are received, OMB recommends that 
written comments be faxed to the Office of Information and Regulatory 
Affairs, OMB, Attn: FDA Desk Officer, FAX: 202-395-7285, or e-mailed to 
<a href="/cdn-cgi/l/email-protection#0f60667d6e507c7a6d62667c7c6660614f60626d216a607f21686079"><span class="__cf_email__" data-cfemail="7b1412091a24080e19161208081214153b141619551e140b551c140d">[email protected]</span></a>.

FOR FURTHER INFORMATION CONTACT:
    For information concerning human drug products: Roger Goetsch, 
Center for Drug Evaluation and Research, Food and Drug Administration, 
10903 New Hampshire Ave., Bldg. 22, Silver Spring, MD, 20993-0002, 301-
770-9299, or
    For information concerning human biological products: Stephen 
Ripley, Center for Biologics Evaluation and Research (HFM-17), Food and 
Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD, 
20852-1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

Table of Contents

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

[[Page 42185]]

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

I. Introduction

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

II. Background

A. Current Postmarketing Safety Reporting Requirements

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

[[Page 42186]]

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

[[Page 42187]]

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

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

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

[[Page 42188]]

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

[[Page 42189]]

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

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

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

D. Electronic Format Submission Initiatives

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

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

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

    \19\ FDA expects that, in the future, all electronic submissions 
to the agency will be sent through the ESG and that use of physical 
media for such submissions will, eventually, be phased-out.
    \20\ FDA is currently accepting electronic submissions using 
either the ICH E2B or ICH E2BM data elements; ICH E2B and ICH E2BM 
are available on the Internet at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm under 
the ICH--Efficacy category or http://www.fda.gov/cber/guidelines.htm 
under the ICH guidance documents category.
    \21\ See footnote number 19 in this document.
    \22\ FDA's AERS electronic submission coordinator may be 
contacted at <a href="/cdn-cgi/l/email-protection#bcddd9cecfd9cfc9defcdad8dd92d4d4cf92dbd3ca"><span class="__cf_email__" data-cfemail="c0a1a5b2b3a5b3b5a280a6a4a1eea8a8b3eea7afb6">[email protected]</span></a>.
---------------------------------------------------------------------------

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

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

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

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

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[[Page 42190]]

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

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

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

    \27\ See footnote number 3 of this document.

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[[Page 42191]]

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

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

III. Description of the Proposed Rule

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

A. Electronic Submission of Postmarketing Safety Reports

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

B. Safety Reports Not Covered by the Proposed Rule

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

C. Waivers

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

[[Page 42192]]

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

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

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

    The term ICSR is used to describe the information contained on 
either an initial or followup report of an individual adverse drug 
experience, currently reported on an FDA Form
    3500A, CIOMS I form, VAERS form, or in electronic format. Given 
that this proposed rule would require that all safety reports be 
submitted in electronic format, we believe describing the safety 
reporting vehicle generically, rather than by reference to the 
associated paper form, is appropriate. Accordingly, we are proposing in 
Sec. Sec.  310.305(b), 314.80(a), and 600.80(a) (with minor 
modifications) to define an ICSR as a description of an adverse drug 
experience related to an individual patient or subject. Because the 
items of information which should be reported in an ICSR are currently 
specified on the paper reporting forms that will no longer be used, we 
are also proposing to add a list of the reportable elements in the 
regulations. Accordingly, proposed Sec. Sec.  310.305(d), 314.80(f), 
and 600.80(f) would provide a detailed list of specific types of 
information in five broad categories that are to be reported on the 
ICSR. The proposed categories, and examples of some of the types of 
information in each category, are as follows:
    <bullet> Patient information (e.g., patient identification code, 
age, gender);
    <bullet> Information about the adverse drug experience (e.g., date 
and description of the adverse drug experience);
    <bullet> Information about the drug (e.g., drug name, dose, 
indication, National Drug Code (NDC) number);
    <bullet> Information identifying the initial reporter (e.g., name 
and contact information); and
    <bullet> Information about the drug's applicant or manufacturer 
(e.g., name and contact information).
    Other than minor wording differences, this proposed list of 
information to be reported is the same as that currently reflected on 
the FDA Form 3500A for postmarketing reporting for drugs and biological 
products. Codification of the ICSR reporting requirements is not 
intended to change the existing obligation of manufacturers, packers, 
or distributors to exercise due diligence for purposes of completing 
all of the applicable elements of an ICSR. The obligation to provide 
all applicable information described in proposed Sec. Sec.  310.305(d), 
314.80(f), or 600.80(f) would be the same as the current obligation to 
complete the FDA Form 3500A.\30\
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    \30\ For FDA's current thinking on ``due diligence,'' see the 
guidance described in footnote 29 of this document.
---------------------------------------------------------------------------

E. Removal of Paper Format Provisions

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

F. Miscellaneous Changes

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

[[Page 42193]]

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

G. Proposed Implementation Timeframe

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

IV. Legal Authority

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

V. Environmental Impact

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

VI. Analysis of Impacts

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

[[Page 42194]]

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

A. Benefits

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

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

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

B. Costs

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

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

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

[[Page 42195]]

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

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

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

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

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

[[Page 42196]]

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

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

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

C. Summary of Benefits and Costs

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

D. Alternatives Considered

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

E. Small Business Impact

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

[[Page 42197]]



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


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

VII. Paperwork Reduction Act of 1995

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

[[Page 42198]]

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

A. Reporting Cost

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

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

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


[[Page 42199]]

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

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

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

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

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

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

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

B. Capital Costs

    As explained in section VI (Analysis of Impacts) of this document, 
total one-time costs to industry under this rule would be between $4.5 
million to $5.6 million; most of these costs would be for changing 
SOPs, setting up systems for submissions, and acquiring an electronic 
certificate. Industry would also incur annual costs of between $133,320 
to $139,380 for Internet upgrades and to maintain electronic 
certificates.
    The information collection provisions of this proposed rule have 
been submitted to OMB for review. Interested persons are requested to 
fax comments regarding information collection by (see DATES section of 
this document), to the Office of Information and Regulatory Affairs, 
OMB. To ensure that comments on the information collection are 
received, OMB recommends that written comments be faxed to the Office 
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, 
FAX: 202-395-7285, or e-mailed to <a href="/cdn-cgi/l/email-protection#16797f6477496563747b7f65657f797856797b743873796638717960"><span class="__cf_email__" data-cfemail="82edebf0e3ddf1f7e0efebf1f1ebedecc2edefe0ace7edf2ace5edf4">[email protected]</span></a>. All 
comments should reference the title of this rule and include the FDA 
docket number found in brackets in the heading of this document.

VIII. Federalism

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

[[Page 42200]]

IX. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

List of Subjects

21 CFR Part 310

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

21 CFR Part 314

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

21 CFR Part 600

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

PART 310--NEW DRUGS

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

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

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


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

* * * * *
    (b) * * *
    Individual case safety report (ICSR). A description of an adverse 
drug experience related to an individual patient or subject.
    (c) Reporting requirements. Each person identified in paragraph 
(c)(1)(i) of this section must submit to FDA adverse drug experience 
information as described in this section. Except as provided in 
paragraph (e)(2) of this section, 15-day ``Alert reports'' and followup 
reports, including ICSRs and any attachments, must be submitted to the 
agency in electronic format as described in paragraph (e)(1) of this 
section.
    (1) Postmarketing 15-day ``Alert reports''. (i) Any person whose 
name appears on the label of a marketed prescription drug product as 
its manufacturer, packer, or distributor must report to FDA each 
adverse drug experience received or otherwise obtained that is both 
serious and unexpected as soon as possible, but no later than 15 
calendar days from initial receipt of the information by the person 
whose name appears on the label. Each report must be accompanied by the 
current content of labeling in electronic format unless it is already 
on file at FDA.
* * * * *
    (3) * * * If a packer or distributor elects to submit these adverse 
drug experience reports to the manufacturer rather than to FDA, it must 
submit, by any appropriate means, each report to the manufacturer 
within 5 calendar days of its receipt by the packer or distributor, and 
the manufacturer must then comply with the requirements of this section 
even if its name does not appear on the label of the drug product. * * 
*
* * * * *
    (4) [Reserved]
* * * * *
    (d) Information reported on ICSRs. ICSRs include the following 
information:
    (1) Patient information.
    (i) Patient identification code;
    (ii) Patient age at the time of adverse drug experience, or date of 
birth;
    (iii) Patient gender; and
    (iv) Patient weight.
    (2) Adverse drug experience.
    (i) Outcome attributed to adverse drug experience;
    (ii) Date of adverse drug experience;
    (iii) Date of report;
    (iv) Description of adverse drug experience;
    (v) Description of relevant tests, including dates and laboratory 
data; and
    (vi) Other relevant patient history, including preexisting medical 
conditions.
    (3) Suspect medication(s).
    (i) Name;
    (ii) Dose, frequency, and route used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) State whether adverse drug experience abated after drug use 
stopped or dose reduced;
    (vi) Lot number;
    (vii) Expiration date;
    (viii) State whether adverse drug experience reappeared after 
reintroduction of drug;
    (ix) NDC number; and
    (x) Concomitant medical products and therapy dates.
    (4) Initial reporter information.
    (i) Name, address, and phone number;
    (ii) Whether the initial reporter is a health professional;
    (iii) Occupation; and
    (iv) Whether the initial reporter also sent a copy of the report to 
FDA.
    (5) Manufacturer, packer, or distributor information.
    (i) Manufacturer, packer, or distributor name and contact office 
address;
    (ii) Telephone number;
    (iii) Report source(s) (e.g., literature, study);
    (iv) Date received by manufacturer, packer, or distributor;
    (v) Basis for marketing if nonapplication product;
    (vi) Type of report being submitted (e.g., 15-day, periodic, 
followup);
    (vii) Adverse drug experience term(s); and
    (viii) Manufacturer report number.
    (e) Electronic format for submissions. (1) Each report required to 
be submitted to FDA under this section, including the ICSR and any 
attached documentation, must be submitted in an electronic format that 
FDA can process, review, and archive. FDA will periodically issue 
guidance on how to provide the electronic submission (e.g., method of 
transmission, media, file formats, preparation and organization of 
files).
    (2) Waivers. Each person identified in paragraph (c)(1)(i) of this 
section may request, in writing, a temporary waiver of the requirements 
in paragraph (e)(1) of this section. These waivers will be granted on a 
limited basis for good cause shown. If the agency grants the waiver, 
the person must submit the reports required under paragraph (c) of this 
section on paper within the required time periods in a form that

[[Page 42201]]

FDA can process, review, and archive. FDA will issue guidance on how to 
provide the paper submission. Procedures for how to request waivers of 
this requirement will be set forth in guidance.
    (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 to each report. The 
preferred methodology for determining the identification code will be 
set forth in guidance. The manufacturer, packer, and distributor should 
include the name of the reporter from whom the information was 
received, unless 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

    3. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a, 
356b, 356c, 371, 374, 379e.
    4. Section 314.80 is amended:
    a. By removing the word ``shall'' each time it appears and by 
adding in its place the word ``must'';
    b. In paragraph (a) by alphabetically adding the definition for 
``Individual case safety report (ICSR)'';
    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'';
    d. By removing the last sentence of paragraph (c)(1)(ii);
    e. By removing paragraph (c)(1)(iv);
    f. By revising paragraph (c) introductory text, the first and third 
sentences of paragraph (c)(1)(iii) introductory text, and paragraph 
(c)(2)(ii);
    g. By removing paragraph (d)(2) and by redesignating paragraph 
(d)(1) as paragraph (d) and revising the first sentence of paragraph 
(d);
    h. By removing paragraph (e)(2) and by redesignating paragraph 
(e)(1) as paragraph (e);
    i. By revising paragraph (f);
    j. By redesignating paragraph (g) through paragraph (k) as 
paragraph (h) through paragraph (l); and revising newly redesignated 
(i);
    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.
* * * * *
    (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 report;
    (iv) Description of adverse drug experience;
    (v) Description of relevant tests, including dates and laboratory 
data; and
    (vi) Other relevant patient history, including preexisting medical 
conditions.
    (3) Suspect medication(s).
    (i) Name;
    (ii) Dose, frequency, and route used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) State whether adverse drug experience abated after drug use 
stopped or dose reduced;
    (vi) Lot number;
    (vii) Expiration date;
    (viii) State whether adverse drug experience reappeared after 
reintroduction of drug;
    (ix) NDC number; and
    (x) Concomitant medical products and therapy dates.
    (4) Initial reporter information.
    (i) Name, address, and phone number;
    (ii) Whether the initial reporter is a health professional;
    (iii) Occupation; and
    (iv) Whether the initial reporter also sent a copy of the report to 
FDA.
    (5) Applicant information.
    (i) Applicant name and contact office address;
    (ii) Telephone number;
    (iii) Report source(s) (e.g., literature, study);
    (iv) Date received by applicant;
    (v) Application number and type;
    (vi) Type of report being submitted (e.g., 15-day, periodic, 
followup);
    (vii) Adverse drug experience term(s); and

[[Page 42202]]

    (viii) Manufacturer report number.
    (g) Electronic format for submissions. (1) Safety report 
submissions, including ICSRs. Any attached documentation, and the 
descriptive information in periodic reports, must be in an electronic 
format that FDA can process, review, and archive. FDA will periodically 
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 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. If the agency grants the waiver, the applicant or 
nonapplicant must submit reports required under this section on paper 
within the required time periods in a form that FDA can process, 
review, and archive. FDA will issue guidance on how to provide the 
paper submission. Procedures for how to request waivers of this 
requirement will be set forth in guidance.
* * * * *
    (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 to each report. The 
preferred methodology for determining the identification code will be 
set forth in guidance. The applicant should include the name of the 
reporter from whom the information was received, unless 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.
* * * * *
    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 act for each of its approved 
abbreviated applications.

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    6. The authority citation for 21 CFR part 600 continues in part to 
read as follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.
* * * * *
    7. Section 600.80 is amended:
    a. By removing the word ``shall'' each time it appears and by 
adding in its place the word ``must'';
    b. By removing the phrase ``licensed manufacturer'' each time it 
appears and by adding in its place the word ``applicant'';
    c. In paragraph (a) by alphabetically adding the definition for 
``Individual case safety report (ICSR)'';
    d. 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'';
    e. In paragraph (c)(1)(ii) by removing the last sentence;
    f. By removing paragraph (c)(1)(iv);
    g. By revising paragraph (c) introductory text, the first and third 
sentences of paragraph (c)(1)(iii) introductory text, and paragraph 
(c)(2)(ii);
    h. By removing paragraph (d)(2) and by redesignating paragraph 
(d)(1) as paragraph (d) and revising the first sentence of paragraph 
(d);
    i. By removing paragraph (e)(2) and by redesignating paragraph 
(e)(1) as paragraph (e);
    j. By revising paragraph (f);
    k. By redesignating paragraph (g) through paragraph (l) as 
paragraph (h) through paragraph (m) and by revising newly redesignated 
paragraph (i); and
    l. By adding new paragraph (g) 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.
* * * * *
    (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 (g)(1) of this section, except as provided in 
paragraph (g)(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, 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, and adverse reaction term(s) for all 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 to be reported on ICSRs. ICSRs include the 
following information:
    (1) Patient information.
    (i) Patient identification code;
    (ii) Patient age at the time of adverse experience, or date of 
birth;

[[Page 42203]]

    (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;
    (v) Description of relevant tests, including dates and laboratory 
data; and
    (vi) Other relevant patient history, including preexisting medical 
conditions.
    (3) Suspect medical product(s).
    (i) Name;
    (ii) Dose, frequency, and route used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) State whether adverse experience abated after product use 
stopped or dose reduced;
    (vi) Lot number;
    (vii) Expiration date;
    (viii) State whether adverse experience reappeared after 
reintroduction of the product;
    (ix) NDC number, or other unique identifier; and
    (x) Concomitant medical products and therapy dates.
    (4) Initial reporter information.
    (i) Name, address, and phone number;
    (ii) Whether the initial reporter is a health professional;
    (iii) Occupation; and
    (iv) Whether the initial reporter also sent a copy of the report to 
FDA.
    (5) Applicant information.
    (i) Applicant name and contact office address;
    (ii) Telephone number;
    (iii) Report source(s) (e.g., literature, study);
    (iv) Date received by applicant;
    (v) Application number and type;
    (vi) Type of report being submitted (e.g., 15-day, periodic, 
followup);
    (vii) Adverse experience term(s); and
    (viii) Manufacturer report number.
    (g) Electronic format for submissions. (1) Safety report 
submissions, including ICSRs and any attached documentation and the 
descriptive information in periodic reports, must be in an electronic 
format that FDA can process, review, and archive. FDA will periodically 
issue guidance on how to provide the electronic submission (e.g., 
method of transmission, media, file formats, preparation and 
organization of files).
    (2) Waivers. Persons subject to the requirements of paragraph (c) 
of this section 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. If the agency grants 
the waiver, the person must submit reports required under this section 
on paper within the required time periods in a form that FDA can 
process, review, and archive. FDA will issue guidance on how to provide 
the paper submission. Requests for waivers must be submitted in 
accordance with Sec.  600.90.
* * * * *
    (i) 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 to each report. The preferred methodology for 
determining the identification code will be set forth in guidance. The 
applicant should include the name of the reporter from whom the 
information was received, unless 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.
* * * * *
    8. Section Sec.  600.81 is amended:
    a. By removing the phrase ``licensed manufacturer'' each time it 
appears and by adding in its place the word ``applicant'';
    b. By designating the existing text as paragraph (a) and by adding 
a new heading for paragraph (a); and
    c. 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 
electronic format in a form that FDA can process, review, and archive. 
FDA will periodically 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. If the 
agency grants the waiver, the applicant must submit reports required 
under this section on paper within the required time period in a form 
that FDA can process, review, and archive. FDA will issue guidance on 
how to provide the paper submission. Requests for waivers must be 
submitted in accordance with Sec.  600.90.


Sec.  600.90  [Amended]

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

    Dated: August 5, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E9-19682 Filed 8-20-09; 8:45 am]
BILLING CODE 4160-01-S


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