Guidance for Industry

Providing Regulatory Submissions in

Electronic Format — Postmarketing

Expedited Safety Reports

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of

publication in the Federal Register of the notice announcing the availability of the draft

guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug

Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be

identified with the docket number listed in the notice of availability that publishes in the Federal

Register.

For questions regarding this draft document send an e-mail (CDER and CBER) to

aersesub@cder.fda.gov, or telephone (CDER) Deborah Yaplee, 301-827-3237 or (CBER)

Michael Fauntleroy, 301-827-5101.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

May 2001

Electronic Submissions
Guidance for Industry

Providing Regulatory Submissions in

Electronic Format — Postmarketing

Expedited Safety Reports

Additional copies are available from:

Office of Training and Communications

Division of Communications Management

Drug Information Branch, HFD-210

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

(Internet) http://www.fda.gov/cder/guidance/index.htm

or

 Office of Communication, Training and

Manufacturers Assistance, HFM-40

Center for Biologics Evaluation and Research

 Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448

Internet: http://www.fda.gov/cber/guidelines.htm.

Fax: 1-888-CBERFAX or 301-827-3844

Mail: the Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

May 2001

Electronic Submissions
Draft — Not for Implementation

TABLE OF CONTENTS

I. INTRODUCTION...............................................................................................................................................................1

II. GENERAL ISSUES ............................................................................................................................................................2

A. PARTS OF A POSTMARKETING EXPEDITED SAFETY REPORT ..................................................................................... 2

B. ELECTRONIC TRANSPORT FORMAT ............................................................................................................................... 2

C. THE ARCHIVAL COPY...................................................................................................................................................... 3

D. NOTIFICATION OF INITIAL ICSR SUBMISSION ............................................................................................................. 3

E. SENDING IN THE SUBMISSION......................................................................................................................................... 3

F. NOTIFICATION OF RECEIPT OF REPORT BY THE FDA.................................................................................................. 4

III. ORGANIZING THE ELECTRONIC SUBMISSION..............................................................................................4

A. ICSR................................................................................................................................................................................... 4

1. Prepare the Data Using the Appropriate E2B/M2 Format ................................................................................4

2. Add EDI Header and Trailer to the ICSR..............................................................................................................6

3. Send the ICSR File with the EDI Header and Trailer..........................................................................................8

B. ICSR ATTACHMENTS...................................................................................................................................................... 8

1. Convert the ICSR Attachment to Portable Document Format (pdf) .................................................................8

2. Enter Identification Information in the pdf Document Information Fields......................................................8

3. Naming the ICSR Attachment...................................................................................................................................9
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Guidance for Industry1 1

2 Providing Regulatory Submissions in Electronic Format –

3 Postmarketing Expedited Safety Reports

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17

18 I. INTRODUCTION

19

20 This is one in a series of guidance documents intended to assist applicants making regulatory

21 submissions in electronic format to the Center for Drug Evaluation and Research (CDER) and

22 the Center for Biologics Evaluation and Research (CBER) in the Food and Drug Administration

23 (FDA). Agency guidance documents on electronic submissions will be updated regularly to

24 reflect the evolving nature of the technology and the experience of those using this technology.

25

26 This guidance discusses general issues related to the electronic submission of postmarketing

27 expedited safety reports for (1) drug products marketed for human use with new drug

28 applications (NDAs) and abbreviated new drug applications (ANDAs), (2) prescription drug

29 products marketed for human use without an approved NDA or ANDA, and (3) therapeutic

30 biological products marketed for human use with biologic license applications (BLAs). This

31 guidance does not apply to vaccines.

32

33 The guidance for industry Providing Regulatory Submissions in Electronic Format — General

34 Considerations (January 1999) discusses issues common to all types of electronic regulatory

35 submissions, such as acceptable file formats, media, and submission procedures (General

Considerations guidance of 1999). 2 36 Information provided in this guidance on electronic

37 submission of postmarketing expedited safety reports supercedes information provided in the

38 General Considerations guidance of 1999 (e.g., number of copies that should be submitted).

 

1

 This guidance has been prepared by the Office of Information Technology (OIT) and Office of Post-marketing

Drug Risk Assessment (OPDRA) in the Center for Drug Evaluation and Research (CDER) in cooperation with the

Office of Biostatistics and Epidemiology in the Center for Biologics Evaluation and Research (CBER).

2

 The FDA is in the process of revising the General Considerations guidance of 1999 and will issue a draft guidance

for public comment summer of 2001.

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's)

current thinking on this topic. It does not create or confer any rights for or on any person and does

not operate to bind FDA or the public. An alternative approach may be used if such approach

satisfies the requirements of the applicable statutes and regulations.
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39 Postmarketing safety reports sent to CDER and CBER for human drug and biological products

40 are loaded into the FDA’s Adverse Event Reporting System (AERS) database. CDER is

41 responsible for oversight of the AERS database and loading of information into it for both CDER

42 and CBER. Applicants sending postmarketing expedited safety reports electronically to the

43 FDA for products regulated by CBER should follow procedures provided for CDER in the

44 General Considerations guidance of 1999 (as well as subsequent versions of the general

45 considerations guidance).

46

47

48 II. GENERAL ISSUES

49

50 Regulations for submission of postmarketing expedited safety reports to CDER and CBER are

51 described in 21 CFR 310.305(c), 314.80(c)(1) and 600.80(c)(1). This section briefly addresses

52 some general issues related to the electronic submission of postmarketing expedited safety

53 reports.

54

55 A. Parts of a Postmarketing Expedited Safety Report

56

57 For the purpose of electronic submissions, we have divided the postmarketing expedited

58 safety report into two parts: (1) the individual case safety report (ICSR) and (2) the

59 attachments to the ICSR (ICSR attachments).

60

61 For purposes of this guidance on electronic submission of postmarketing expedited safety

62 reports, an ICSR contains data elements as defined in the guidance for industry entitled

63 E2B Data Elements for Transmission of Individual Case Safety Reports (January 1998)

64 (E2B). The information described in the E2B guidance was developed by the

65 International Conference on Harmonisation of Technical Requirements for Registration

66 of Pharmaceuticals for Human Use (ICH) E2B working group. In November 2000, this

67 group revised E2B (E2BM). The FDA will implement E2BM in the near future. At that

68 time, the Agency will support use of both the E2B and E2BM data elements.

69

70 ICSR attachments include published articles that must accompany ICSRs based on

71 scientific literature (21 CFR 314.80(d) and 600.80(d)) as well as other supporting

72 information such as relevant hospital discharge summaries and autopsy reports/death

73 certificates.

74

75 B. Electronic Transport Format

76

77 The electronic transport format to be used with the E2B data elements is defined in the

78 ICH document entitled M2 Electronic Transmission of Individual Case Safety Report

79 Message Specification version 2.24 (ICH ICSR DTD Version 2.0) (M2 Specification

80 version 2.24, DTD version 2.0), which can be found at www.fda.gov/cder/m2. In

81 November 2000, the ICH M2 working group revised the specifications for electronic

submission of individual case safety reports consistent with E2BM.3 82 The revised

 

3 M2 Electronic Transmission of Individual Case Safety Reports Message Specification version 2.3 (ICH ICSR DTD

Version 2.1) (M2 Specification version 2.3, DTD version 2.1).
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83 electronic specifications will be implemented by the FDA concurrently with

84 implementation of E2BM.

85

86 C. The Archival Copy

87

88 Once we have identified the ICSR and/or ICSR attachments in public docket number

89 92S-0251 as submission types that we can accept in an electronic format, you can provide

them in an electronic format in place of the currently required paper copies.4 90 Until that

91 time, if you wish to submit electronically, you must also submit a paper copy for the

archival file.5 92

93

94 D. Notification of Initial ICSR Submission

95

96 Prior to the first time that you submit an ICSR electronically to the FDA, you should

97 notify the AERS electronic submission coordinator of your intent at

98 aersesub@cder.fda.gov. It is not necessary to contact the AERS electronic submission

99 coordinator prior to sending an ICSR to the FDA for subsequent electronic submissions

100 of ICSRs.

101

102 E. Sending in the Submission

103

104 You can send an ICSR to the FDA using either physical media (i.e., floppy disk, CD105 ROM, or digital tape) or the FDA’s Electronic Data Interchange (EDI) gateway. We

106 prefer that you send the ICSR using the EDI gateway because this allows the most

107 efficient processing of the reports. ICSR attachments, however, should be sent only on

108 physical media.

109

110 For information on providing submissions using the EDI gateway, contact the AERS

electronic submission coordinator at aersesub@cder.fda.gov. 111

112

113 Information on preparing and sending submissions on physical media can be found in the

General Considerations guidance of 1999.6 114 Current regulations require that

115 postmarketing expedited safety reports bear prominent identification as to their contents

(i.e., “15-day Alert report,” or “15-day Alert report-followup”). 7 116 When sending a report

117 to the FDA on physical media, applicants should identify the media as described in the

118 current regulations (i.e., “15-day Alert report,” or “15-day Alert report-followup”).

119

 

4

 See 21 CFR 310.305(d), 314.80(f) and 600.80(f) for requirement to submit postmarketing safety reports on an

FDA Form 3500A.

5

 See 21 CFR 11.2(b)(2).

6

 As described previously in section I of this guidance, applicants with approved applications for products regulated

by CBER should follow procedures described in the General Considerations guidance of 1999 for CDER.

7

 See 21 CFR 310.305(c)(4), 314.80(c)(1)(iv), and 600.80(c)(1)(iv).
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120 F. Notification of Receipt of Report by the FDA

121

122 Once a submission reaches the EDI gateway and is successfully recognized and

123 decrypted, an EDI gateway acknowledgement will be returned to the sender. The date of

124 this acknowledgement will serve as the official receipt date of the submission.

125

126 After receipt of the submission, we will load the ICSRs into the AERS database. For

127 submissions sent via the EDI gateway, an automated standard generalized markup

128 language (SGML) acknowledgment message, which gives the status of each report in the

129 transmission, will be returned to you via the gateway.

130

131 For submissions sent on physical media, the Agency will determine the receipt date as it

132 does with submissions sent to the FDA on paper (i.e., receipt date is the date it arrives at

133 the Agency). The Agency will only contact you if there are problems with the format of

134 the report or if the report does not load properly into the AERS database. We will contact

135 you by phone or email, describe the problem, and request a resubmission of the report in

136 the proper format. This resubmission should take place as soon as possible.

137

138

139 III. ORGANIZING THE ELECTRONIC SUBMISSION

140

141 A. ICSR

142

143 The following describes the steps you should take to prepare and send the ICSR in an

144 electronic format.

145

146 1. Prepare the Data Using the Appropriate E2B/M2 Format

147

148 Whether you are providing the ICSR on physical media or sending it using the EDI

149 gateway, you should provide the ICSR as an SGML file using the data elements and

150 electronic transport format currently accepted by the FDA (e.g., currently, the FDA is

151 accepting E2B data elements with the M2 Specification version 2.24, DTD version 2.0

electronic transport format.8 152 See sections II.A and II.B in this guidance).

153

154 a. Coding reactions and events

155

156 Section B.2 of E2B is designated for reaction/event terms. For these fields, the FDA

prefers that applicants use the Medical Dictionary for Regulatory Activities (MedDRA).9 157

158 For the E2B field, B.2.i.1, you should insert the lowest level term (LLT) in MedDRA that

159 most closely corresponds to the term reported by the primary source. For the E2B field,

 

8

 Once the Agency has implemented them, the FDA will also accept E2BM data elements with the M2

Specification version 2.3, DTD version 2.1 electronic transport format.

9

 Companies can license MedDRA from an international maintenance and support services organization (MSSO)

(toll free number 877-258-8280 (703-345-7799 in Washington, D.C. area), fax 703-345-7755, e-mail

subscrib@meddramsso.com, Internet at www.meddramsso.com) .
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160 B.2.i.2, you should insert the preferred term (PT) in MedDRA that corresponds to the

LLT used in B.2.i.1.10 161 If you do not have access to MedDRA, you should populate the

162 E2B field, B.2.i.2, with a reaction term (e.g., a COSTART term, a WHOART term) and

163 leave the E2B field, B.2.i.1, blank.

164

165 b. Identification numbers

166

167 Section A.1 of E2B is designated for identification numbers. You should include in the

168 A.1.10 field a concatenation of the country code, sender identification, and report

169 number. E2B fields A.1.10.1, A.1.10.2, and A.1.11.2 should only be filled in if a report is

170 received by one entity (e.g., the FDA, a company) AND the entity subsequently transmits

the report to one or more other entities. 11 171

172

173 • E2B field A.1.10.1 should be filled in by the FDA (or other regulatory authority) if:

174 1. it receives a direct report from a health care professional or consumer AND

175 2. the report is subsequently sent to one or more other entities.

176

177 • E2B field A.1.10.2 should be filled in by a company if:

178 1. it is the first company to receive a direct report from a health care professional or

179 consumer OR

180 2. it is the first company to receive an ICSR from the FDA (or other regulatory authority)

181 AND

182 3. the report is subsequently sent to one or more new entities.

183

184 • E2B field A.1.11.2 should be filled in by a company if:

185 1. it receives an ICSR from another company AND

186 2. the report is subsequently sent to one or more new entities.

187

188 The A.1.11.2 field should be used by all companies that receive an ICSR from another

189 company (i.e., this field may contain multiple identification numbers). Possible scenarios

190 for populating fields A.1.10.1, A.1.10.2, and A.1.11.2 are shown in Table 1.

 

10 If you are using subsequent versions of E2B (e.g., E2BM), you should follow the explicit guidance for populating

the B.2 fields as described in the document.

11 If you are using subsequent versions of E2B (e.g., E2BM), you should follow explicit guidance for populating the

A.1 fields as described in the document.
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191

192 Table 1: Example Scenarios for Populating Identification Fields

Path of ICSR Who provides identification number for fields

A.1.10.1 A.1.10.2 A.1.11.2

Scenario 1

A direct report from a health care

professional or consumer is sent to the

FDA and subsequently transmitted to

Company A

FDA empty empty

Company A received the report from the

FDA and subsequently transmitted it to

Company B

FDA Company A empty

Company B received the same report from

Company A and subsequently transmitted

it to Company C and Company D

FDA Company A Company B

Scenario 2

A direct report from a health care

professional or consumer is sent to

Company A and subsequently transmitted

to Company B

Empty Company A Empty

Company B received the report from

Company A and subsequently transmitted

it to Company C and Company D

Empty Company A Company B

Company D received the report from

Company B and subsequently transmitted

it to Company E

Empty Company A Company B

Company D

193

194

195 The identification numbers used for followup reports should remain unchanged from

196 those included in the original report. Once a field is populated, you should not change

197 the information contained in it for any subsequent report. If you wish to make a

198 correction, you should provide corrected information in a new field. For example, if the

199 FDA (or any other regulatory authority) is not the sender of the original report, the field

200 in A.1.10.1 should not be populated in any followup reports. You should capture your

201 identification number in A.1.10.2 or A.1.11.2.

202

203 2. Add EDI Header and Trailer to the ICSR

204

205 We use an EDI header and trailer to process the ICSR whether you provide the ICSR on

206 physical media or send it using the EDI gateway. For this reason, you should add an EDI

207 header and trailer to all ICSR files.

208

209 EDI headers and trailers are made up of a series of data elements separated by plus (+)

210 signs. A colon should separate segments of the individual data elements. An apostrophe

211 should be used to terminate the header, body of the message, and the trailer.
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212

213 The ICSR should be preceded by the EDIFACT UNB header and followed by the UNZ

214 trailer. The data that should be used in headers and trailers are shown in the following

215 tables:

216

217 Table 2 EDIFACT UNB Header Information

Description Code Comments

Identification of the start

of the UNB header

UNB The code for the start of the UNB header

should be UNB in upper case letters

Version of the standard

of the UNB header

UNOB:1 The current version code should be UNOB

in upper case letters

Interchange sender

identification code and

sender code qualifier

xxxxxxx:01 xxxxxxx should be the number assigned to

your company by Dun and Bradstreet

Information Services. (For industry

sending to the FDA, the sender code

qualifier is 01.)

Interchange recipient FDAEDI.xxxx:zz xxxx should be the code for the receiving

center (CDER, CBER, CDRH, CVM,

CFSAN)

Date and time of

preparation

yymmdd:hhmm For now, a two-digit designation should be

used for the year

Interchange control

reference

Up to 14

alphanumeric

characters

You should assign a unique reference

number for each interchange. Otherwise

the system will not recognize the

transmission as new

218

219

220 Table 3 UNZ Trailer Information

Description Code Comments

Identification of

the start of the

trailer

UNZ The code for the start of the trailer is UNZ in

upper case letters

Interchange

control count

Up to 6 numerical

characters

Counts either the number of messages or the

number of functional groups within the

interchange. Usually, this is 1

Interchange

control reference

Up to 14 alphanumeric

characters

This should be the same as the interchange

control reference in the UNB header

221

222

223 The following is an example of a complete message with a UNB header and UNZ trailer.

224 The message “this is a test text” was sent to CDER on April 27, 2000 at 11 AM. The

225 company DUNS number was 000000000. The reference number for the message was

10001226
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227

228 UNB+UNOB:1+000000000:01+FDAEDI.CDER:zz+000427:1100+10001

229 'this is a test text'

230 UNZ+1+10001'

231

232 3. Send the ICSR File with the EDI Header and Trailer

233

234 If you choose to submit the ICSR on physical media, you should use edi as the extension

235 for each file. The name of the file should be 40 characters or less excluding the three236 digit extension. You should place the edi files on the physical media along with any

237 ICSR attachment files. You should follow the General Considerations guidance of 1999

for preparing and sending physical media.12 238

239

240 If you choose to submit the ICSR over the EDI gateway, contact the AERS electronic

241 submission coordinator at aersesub@cder.fda.gov for additional guidance.

242

243 B. ICSR Attachments

244

245 The following describes the steps you should take to prepare and send attachments to an

246 ICSR in an electronic format.

247

248 1. Convert the ICSR Attachment to Portable Document Format (pdf)

249

250 We are able to archive ICSR attachments in pdf format. You should provide an individual

251 pdf file for each attachment to an ICSR. If there is more than one piece of information in

252 an ICSR attachment, include each piece of information in the same pdf file and provide a

253 pdf bookmark to each piece of information. For example, if there is a hospital discharge

254 summary and an autopsy report for a single ICSR, you should include both in a single pdf

255 file with a bookmark to the hospital discharge summary and a bookmark to the autopsy

256 report.

257

258 2. Enter Identification Information in the pdf Document Information Fields

259

260 Each pdf file contains fields that can be filled in by the author of the document. We use

261 these fields in our system to locate and retrieve the attachments to specific ICSRs. To

262 help us match the attachment to the ICSR, you should fill in the pdf document

263 information fields with the appropriate E2B/E2BM data elements included in the ICSR as

264 described in table 4.

 

12 As described previously in section I of this guidance, applicants with approved applications for products

regulated by CBER should follow procedures described in the General Considerations guidance of 1999 for CDER.
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265 Table 4: Document Information Fields in ICSR Attachments

Document

information field

What information should be included in the field*

Title Sender’s identification number (A.1.10.2)

Subject FDA identification number (A.1.10.1) and Sender’s identification

number (A.1.10.2)

Author Other identification number (A.1.11.2 )

Keywords Date of receipt of the most recent information for this ICSR (A.1.7)

266

267 * The information in the parentheses refer to the data elements in E2B

268

269 3. Naming the ICSR Attachment

270

271 To help us match the attachment to the ICSR, you should use the manufacturer’s control

272 number for the ICSR as the file name for the ICSR attachment with pdf as the extension.

273