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.

Proposed Rules Federal Register

42184 

Vol. 74, No. 161 

Friday, August 21, 2009 

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. 

SUMMARY: The Food and Drug 

Administration (FDA) is proposing to 

amend its postmarketing safety 

reporting regulations for human drug 

and biological products to require that 

persons subject to mandatory reporting 

requirements submit safety reports in an 

electronic format that FDA can process, 

review, and archive. FDA is taking this 

action to improve the agency’s systems 

for collecting and analyzing 

postmarketing safety reports. The 

proposed change would help the agency 

to more rapidly review postmarketing 

safety reports, identify emerging safety 

problems, and disseminate safety 

information in support of FDA’s public 

health mission. In addition, the 

proposed amendments would be a key 

element in harmonizing FDA’s 

postmarketing safety reporting 

regulations with international standards 

for the electronic submission of safety 

information. 

DATES: Submit written or electronic 

comments on the proposed rule by 

November 19, 2009. Submit comments 

on information collection issues under 

the Paperwork Reduction Act of 1995 by 

September 21, 2009, (see section ‘‘VII. 

Paperwork Reduction Act of 1995’’ of 

this document). See section III.G of this 

document for the proposed effective 

date of a final rule based on this 

proposed rule. 

ADDRESSES: You may submit comments, 

identified by Docket No. FDA–2008–N– 

0334 and/or RIN number 0910–AF96, by 

any of the following methods, except 

that comments on information 

collection issues under the Paperwork 

Reduction Act of 1995 must be 

submitted to the Office of Regulatory 

Affairs, Office of Management and 

Budget (OMB) (see the ‘‘Paperwork 

Reduction Act of 1995’’ section of this 

document). 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

Written Submissions 

Submit written submissions in the 

following ways: 

• FAX: 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 email. 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 

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 


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1For purposes of this preamble, the term adverse 

drug experience includes an adverse experience 

associated with use of a biological product. 

2Additional information regarding the AERS 

database may be found at: http://www.fda.gov/cder/ 

aers/default.htm. 

3The 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. 

4For § 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 (§§ 314.80(d) and 600.80(d)), as well as 

other supporting information such as relevant 

Continued 

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 

experiences1 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. 

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

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. 

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 ICHrecommended 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 §§ 310.305, 

314.80, 314.98, and 600.80, 

manufacturers, packers, distributors,4


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hospital discharge summaries and autopsy reports/ 

death certificates. 

7Health 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. 

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/Guidance

ComplianceRegulatoryInformation/Guidances/ 

default.htm under ‘‘Procedural.’’ 

and applicants5 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 attachments6) 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. 

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 

(§§ 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 §§ 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 § 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 §§ 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. 

c. Distribution reports. In addition to 

periodic reports, under § 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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9The 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. 

11The VAERS form can be accessed on the 

Internet at http://secure.vaers.org/vaersdata

entryintro.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.) 

12Report on-line at https://secure.vaers.org. 

13MedDRA 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. 

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 §§ 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 form9 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 §§ 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. 

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 form11 or reported on-line using 

the VAERS secure web-based system12. 

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. 

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 ICH13. 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. 

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,’’ 


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14These resources are available on the Internet at 

(IOM response) http://www.fda.gov/downloads/ 

drugs/drugsafety/postmarketingdrugsafety

informationforpatientsandproviders/ 

UCM171627.pdf, (strategic plan) http:// 

www.fda.gov/ope/stratplan07/stratplan07.htm, and 

(guidance) http://www.fda.gov/Drugs/Guidance

ComplianceRegulatoryInformation/Guidances/ 

default.htmunder ‘‘Clinical/Medical.’’ 

15See section II.A.1.b of this preamble for a 

description of periodic ICSRs. 

16Postmarketing 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). 

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. 

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 reports15) 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. 

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 ICHcompatible 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 ICHcompatible 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 


CPrice-Sewell on DSKGBLS3C1PROD with PROPOSALS
Federal Register / Vol. 74, No. 161 / Friday, August 21, 2009 / Proposed Rules 42189 

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/Guidance

ComplianceRegulatoryInformation/Guidances/ 

default.htm under the ICH—Efficacy category or 

http://www.fda.gov/cber/guidelines.htm under the 

ICH guidance documents category. 

18 Docket No. FDA–1992–S–0039 (formerly 

Docket No. 1992S–0251) can be accessed on the 

Internet at http://www.regulations.gov. 

19FDA 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. 

20FDA 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. 

21See footnote number 19 in this document. 

22FDA’s AERS electronic submission coordinator 

may be contacted at aersesub@fda.hhs.gov. 

23See 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. 

25The 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. 

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 E2BM17 compliant ICSRs be 

submitted in electronic format either by 

the Internet or by physical media. 

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 format18. 

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., CDROM, 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 coordinator22 to establish an 

ESG connection with FDA’s network. 

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 M224 ). 

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. 

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 Webbased 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. 


CPrice-Sewell on DSKGBLS3C1PROD with PROPOSALS
42190 Federal Register / Vol. 74, No. 161 / Friday, August 21, 2009 / Proposed Rules 

26The 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. 27See footnote number 3 of this document. 

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. 

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 generallyrecognized 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. 


CPrice-Sewell on DSKGBLS3C1PROD with PROPOSALS
Federal Register / Vol. 74, No. 161 / Friday, August 21, 2009 / Proposed Rules 42191 

28NIST, 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. 

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)–80028 series 

security certification standards. 

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 

§§ 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 §§ 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 §§ 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 

§ 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 

§§ 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 § 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 

(§ 312.32); 

• Safety update reports for drugs 

(§ 314.50(d)(5)(vi)(b)); 

• Approved NDA and BLA annual 

reports (§§ 314.81(b)(2) and 601.28 (21 

CFR 601.28)); 

• Biological product deviation reports 

(BPDRs) (§§ 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 tissuebased 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 

(§ 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 

§§ 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 


CPrice-Sewell on DSKGBLS3C1PROD with PROPOSALS
42192 Federal Register / Vol. 74, No. 161 / Friday, August 21, 2009 / Proposed Rules 

29FDA’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/Guidance

ComplianceRegulatoryInformation/Guidances/ 

default.htm under ‘‘Procedural’’ or at http:// 

www.fda.gov/cber/guidelines.htm. 

30For FDA’s current thinking on ‘‘due diligence,’’ 

see the guidance described in footnote 29 of this 

document. 

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. 

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 §§ 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 

§§ 310.305(d), 314.80(f), and 600.80(f) 

would provide a detailed list of specific 

types of information in five broad 

categories that are to be reported on the 

ICSR. The proposed categories, and 

examples of some of the types of 

information in each category, are as 

follows: 

• Patient information (e.g., patient 

identification code, age, gender); 

• Information about the adverse drug 

experience (e.g., date and description of 

the adverse drug experience); 

• Information about the drug (e.g., 

drug name, dose, indication, National 

Drug Code (NDC) number); 

• Information identifying the initial 

reporter (e.g., name and contact 

information); and 

• Information about the drug’s 

applicant or manufacturer (e.g., name 

and contact information). 

Other than minor wording 

differences, this proposed list of 

information to be reported is the same 

as that currently reflected on the FDA 

Form 3500A for postmarketing reporting 

for drugs and biological products. 

Codification of the ICSR reporting 

requirements is not intended to change 

the existing obligation of manufacturers, 

packers, or distributors to exercise due 

diligence for purposes of completing all 

of the applicable elements of an ICSR. 

The obligation to provide all applicable 

information described in proposed 

§§ 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

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 §§ 310.305(d), 314.80(f) and 

600.80(f) the provisions specifically 

describing paper submissions and 

replace them with a new paragraph 

(proposed §§ 310.305(e)(1), 314.80(g)(1) 

and 600.80(g)(1)), which states that 

ICSRs and any attachments must be 

submitted to FDA in an electronic 

format that we can process, review, and 

archive. In addition, we are proposing to 

revise current regulations to remove or 

modify the following references or 

provisions that are specific to paper 

formats: 

• References to the number of paper 

copies required for safety report 

submissions (§§ 310.305(c) , 314.80(c), 

and 600.80(c)); 

• The requirement to mark paper 

reports to identify their contents as ‘‘15- 

day Alert report’’ or ‘‘15-day Alert 

report-followup,’’ (§§ 310.305(c)(4), 

314.80(c)(1)(iv), 600.80(c)(1)(iv)); 

• The requirement to use FDA Form 

3500A, CIOMS I form, or VAERS form 

or to determine an appropriate 

alternative format for voluntary 

submission in electronic format 

(§§ 310.305(d)(1) and (3); 314.80(f)(1) 

and (3), and 600.80(f)(1) and (3)); 

• The reference to FDA Form 3500A 

or other paper forms designated for 

adverse drug experience reporting by 

FDA for ICSRs that are submitted as part 

of periodic reporting requirements 

(§§ 314.80(c)(2)(ii)(b) and 

600.80(c)(2)(ii)(B)); and 

• The requirement for identifying 

reports of adverse drug experiences that 

occur in postmarketing studies by 

separating and marking them 

(§§ 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 

§§ 310.305, 314.80, 314.98, and 600.80 

by replacing the word ‘‘shall’’ with the 

word ‘‘must’’ except in the first sentence 

of §§ 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 § 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 §§ 600.80, 600.81 and 

600.90. 

Current §§ 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 § 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) 


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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 

§§ 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 §§ 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 

§§ 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 §§ 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 

§§ 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. 


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31Cost to convert paper reports to electronic 

format from FDA AERS data entry contract. 

32Wage derived from 2007 Bureau of Labor 

Statistics Occupation Employment Statistics 

Survey, standard occupation code 11–3042, training 

manager for pharmaceutical medicine and 

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. 

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


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Federal Register / Vol. 74, No. 161 / Friday, August 21, 2009 / Proposed Rules 42195 

manufacturing—mean wage rate $48.73 + 40 

percent for nonwage benefits and rounded to $68, 

at www.bls.gov. 

33Eastern 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. 

34See http://www.fda.gov/esg/ 

default.htm#tutorials and http://www.fda.gov/esg/ 

account.htm. 

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). 

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). 

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 onehalf 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. 


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35Pociask, 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. 

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). 

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 highspeed 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. 


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TABLE 1.—ONE-TIME COSTS BY FIRM TYPE1

Type of Firm 

Total 

number of 

firms 

Establishing 

e-submission capability 

Acquiring 

e-certificate1

PDF files 

Total 

Modifying 

SOPs Low High ICH Method Low High low high 

Drug and biologic products subject to parts 

310, 314, and 600 600 $680,000 $272,000 $544,000 $340,000 $7,200 $8,400 $201,600 $1,500,800 $1,774,000 

Nonprescription drug 

products marketed 

without an approved 

application 400 1,088,000 217,000 435,200 4,800 5,600 134,400 1,444,800 1,663,200 

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 

years $553,286 $656,205 

Annualized at 7% over 10 

years $647681 $796,967 

1This 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

Type of Firm 

Electronic Certificate 

Internet access 

Total 

Low High Low High 

Drug and biologic products subject to 

parts 310, 314, and 600 $10,800 $12,600 $28,800 $39,600 $41,400 

Nonprescription drug products marketed 

without an approved application 7,200 8,400 19,200 26,400 27,600 

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 §§ 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 § 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 

§§ 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, 


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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 § 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 

§§ 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 

§§ 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 §§ 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

21 CFR Sections Number of 

Respondents 

Number of 

Responses Per 

Respondent 

Total Annual 

Responses 

Hours per 

Response Total Hours 

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. 379aa((b) and (c)) 1 1 1 1 1 

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 

21 CFR Sections Number of 

Respondents 

Number of 

Responses Per 

Respondent 

Total Annual 

Responses 

Hours per 

Response Total Hours 

Form 3500A (§§ 310.305, 314.80, 

314.98, & 600.80) 600 765 459,102 1.1 505, 012 


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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 

21 CFR Sections Number of 

Respondents 

Number of 

Responses Per 

Respondent 

Total Annual 

Responses 

Hours per 

Response Total Hours 

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 

21 CFR Sections Number of 

Respondents 

Number of 

Responses Per 

Respondent 

Total Annual 

Responses 

Hours per 

Response Total Hours 

600.80(c)(1) & 600.80(e) 88 270.85 23,835 1 23,835 

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 

21 CFR Sections Number of 

Respondents 

Number of 

Responses Per 

Respondent 

Total Annual 

Responses 

Hours per 

Response Total Hours 

Reports of serious adverse drug events 

(21 U.S.C. 379aa((b) and (c)) 50 250 12.500 2 25,000 

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 onetime 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 

oira_submission@omb.eop.gov. 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. 


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42200 Federal Register / Vol. 74, No. 161 / Friday, August 21, 2009 / Proposed Rules 

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: 

§ 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 


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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: 

§ 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 


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42202 Federal Register / Vol. 74, No. 161 / Friday, August 21, 2009 / Proposed Rules 

(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: 

§ 314.98 Postmarketing reports. 

(a) Each applicant having an approved 

abbreviated new drug application under 

§ 314.94 that is effective must comply 

with the requirements of § 314.80 

regarding the reporting and 

recordkeeping of adverse drug 

experiences. 

(b) Each applicant must make the 

reports required under § 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: 

§ 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; 


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

§ 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 § 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: 

§ 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 § 600.90. 

§ 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 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 803 

[Docket No. FDA–2008–N–0393] 

RIN 0910–AF86 

Medical Device Reporting: Electronic 

Submission Requirements 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is proposing to 

amend its postmarket medical device 

reporting regulation to require that 

manufacturers, importers, and user 

facilities submit mandatory reports of 

individual medical device adverse 

events, also known as medical device 

reports (MDRs) to the agency in an 

electronic format that FDA can process, 

review, and archive. Mandatory 

electronic reporting would improve the 

agency’s process for collecting and 

analyzing postmarket medical device 

adverse event information. The 

proposed regulatory changes would 

provide the agency with a more efficient 

data entry process that would allow for 

timely access to medical device adverse 

event information and identification of 

emerging public health issues. 

Elsewhere in this issue of the Federal 

Register, FDA is also announcing a draft 

guidance document that provides 

recommendations on how to prepare 

and submit electronic MDRs to FDA in 

a manner that satisfies the requirements 


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