Postmarketing Safety Reports for Human Drug and Biological Products; Electronic Submission Requirements, 42184-42203 [E9-19682]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 74, Number 161 (Friday, August 21, 2009)]
[Proposed Rules]
[Pages 42184-42203]
From the Federal Register Online via the Government Printing 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:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     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 
https://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 https://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 
oira_submission@omb.eop.gov.

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: https://www.fda.gov/cder/aers/default.htm.
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    FDA is proposing to require use of an electronic format for the 
submission of postmarketing safety reports (see section II of this 
document), which would be an important step toward improving the 
agency's systems for collecting and analyzing these reports. The 
proposal would:
     Eliminate the time and costs associated with submitting 
paper reports (for industry) and converting data from paper reports 
into electronic format for review and analysis (for the agency),
     Expedite the agency's access to safety information and 
provide data to the agency in a format that would support more 
efficient and comprehensive reviews, and
     Enhance our ability to rapidly communicate information 
about suspected problems to health care providers, consumers, 
applicants, and sponsors within the United States and internationally 
in support of FDA's public health mission.
    The proposed rule would require that postmarketing safety reports 
be submitted to us in an electronic format that we can process, review, 
and archive. Consistent with FDA's current practice for firms that 
already submit these reports in electronic format voluntarily, 
technical specifications referenced in FDA guidance documents will 
describe how to submit such reports to the agency.\3\ As necessary, the 
agency will revise the technical specifications referenced in FDA 
guidance documents to address changing technical specifications or any 
additional specifications that may be needed for mandatory electronic 
safety reporting. Using guidance documents to communicate these 
technical specifications will permit FDA to be more responsive to 
rapidly occurring changes in the technological environment.
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    \3\ The most current information on submitting postmarketing 
safety reports in electronic format can be found in the draft 
guidance on ``Providing Regulatory Submissions in Electronic 
Format--Postmarketing Individual Case Safety Reports'' (73 FR 33436, 
June 12, 2008) and the ``Periodic safety update reports'' section of 
the guidance on ``Providing Regulatory Submissions in Electronic 
Format--Human Pharmaceutical Product Applications and Related 
Submissions Using the eCTD Specifications'' (Revision 2, June 2008). 
We intend to finalize the draft guidance document in the near 
future.
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    Currently, the technical specifications referenced in guidance 
documents rely upon and adopt certain safety reporting and transmission 
standards recommended by the International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH). ICH was formed to facilitate the harmonization of technical 
requirements for the registration of pharmaceutical products among the 
three ICH regions: The European Union, Japan, and the United States. In 
this proposed rule, we reaffirm our intention to continue to rely on 
these ICH-recommended standards, in addition to providing other options 
(see section II.D.1 of this document). We believe the continued use of 
ICH standards will promote harmonization of safety reporting among 
regulatory agencies and facilitate the international exchange of 
postmarketing safety information. Accordingly, this proposed rule is 
consistent with ongoing agency initiatives to encourage the widest 
possible use of electronic technology and to promote international 
harmonization of safety reporting for human drug and biological 
products through reliance on ICH standards. (See section II.C.3 of this 
document for additional discussion of ICH.).
    In this document, we provide background information on the current 
status of FDA's postmarketing safety reporting requirements (current 
regulations and previously proposed revisions) (sections II.A and II.B 
of this document). We also discuss the rationale for proposing this 
rule (section II.C of this document). Additionally, we describe 
electronic postmarketing safety reporting initiatives (section II.D of 
this document), including an advanced notice of proposed rulemaking 
(ANPRM) that we issued in 1998. Finally, we describe the proposed rule 
(section III of this document).

II. Background

A. Current Postmarketing Safety Reporting Requirements

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

[[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 https://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

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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 https://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 https://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) https://www.fda.gov/downloads/drugs/drugsafety/postmarketingdrugsafetyinformationforpatientsandproviders/UCM171627.pdf, (strategic plan) https://www.fda.gov/ope/stratplan07/stratplan07.htm, and (guidance) https://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.
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    \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 https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm under the ICH--Efficacy category or https://www.fda.gov/cber/guidelines.htm under the ICH guidance documents 
category.
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    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 https://www.regulations.gov.
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    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.
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    \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 https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm under 
the ICH--Efficacy category or https://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 aersesub@fda.hhs.gov.
---------------------------------------------------------------------------

    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.
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    \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 https://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.
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    \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.
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    \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.
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III. Description of the Proposed Rule

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

A. Electronic Submission of Postmarketing Safety Reports

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

B. Safety Reports Not Covered by the Proposed Rule

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

C. Waivers

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

[[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 
cou