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Guidance for Industry

Providing Regulatory Submissions in

Electronic Format —

General Considerations

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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 contact (CBER) Michael Fauntleroy 301-827-5132,

(CDER) Randy Levin 301-594-5411, (CDRH) Stuart Carlow, (CFSAN) JoAnn Ziyad 202-418-

3116, (CVM) Elizabeth L. Parbuoni 301-827-4621. 

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Biologic Evaluation and Research (CBER)

Center for Drug Evaluation and Research (CDER)

Center for Devices and Radiological Health (CDRH)

Center for Food Safety and Applied Nutrition (CFSAN)

Center for Veterinary Medicine (CVM)

October 2003

Electronic Submissions

Revision 1
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Guidance for Industry

Providing Regulatory Submissions in

Electronic Format —

General Considerations

Additional copies are available at:

http://www.fda.gov/cder/guidance/index.htm

or

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

or

http://www.fda.gov/cvm/guidance/guidance.html

or

http://www.cfsan.fda.gov/~dms/guidance.html

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Biologic Evaluation and Research (CBER)

Center for Drug Evaluation and Research (CDER)

Center for Devices and Radiological Health (CDRH)

Center for Food Safety and Applied Nutrition (CFSAN)

Center for Veterinary Medicine (CVM)

October 2003

Electronic Submissions

Revision 1
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TABLE OF CONTENTS

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

II. BACKGROUND ................................................................................................................... 2

III. HOW DO ELECTRONIC SUBMISSIONS RELATE TO 21 CFR PART 11?.............. 2

IV. WHAT FILE FORMATS SHOULD I USE FOR ELECTRONIC DOCUMENTS? ..... 2

A. Version ............................................................................................................................................3

B. Fonts................................................................................................................................................3

C. Page Orientation ............................................................................................................................4

D. Page Size and Margins...................................................................................................................5

E. Source of Electronic Document ....................................................................................................5

F. Methods for Creating PDF Documents and Images ...................................................................5

G. Hypertext Linking and Bookmarks .............................................................................................6

H. Page Numbering.............................................................................................................................7

I. Document Information Fields.......................................................................................................8

J. Open Dialog Box ............................................................................................................................8

K. Naming PDF Files ..........................................................................................................................8

L. Security ...........................................................................................................................................8

M. Indexing PDF Documents..............................................................................................................8

N. Plug Ins ...........................................................................................................................................9

V. WHAT FILE FORMATS SHOULD I USE FOR ELECTRONIC DATASETS?.......... 9

A. SAS System XPORT Transport Format (Version 5 SAS Transport Format) .........................9

B. XML .............................................................................................................................................. 11

C. SGML............................................................................................................................................ 11

D. Molfiles.......................................................................................................................................... 12

VI. WHAT ARE THE PROCEDURES FOR SENDING ELECTRONIC SUBMISSIONS

FOR ARCHIVE? ........................................................................................................................ 12

A. Electronic Transmission.............................................................................................................. 12

B. Physical Media ............................................................................................................................. 13

VII. WHAT IF I HAVE A QUESTION?.............................................................................. 16

A. CBER ............................................................................................................................................ 16

B. CDER ............................................................................................................................................ 16
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C. CDRH............................................................................................................................................ 16

D. CFSAN .......................................................................................................................................... 16

E. CVM.............................................................................................................................................. 16

APPENDIX A: ADDITIONAL INFORMATION ON PROVIDING ELECTRONIC

SUBMISSIONS ON PHYSICAL MEDIA................................................................................ 17
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1

Guidance for Industry1 1

2 Providing Regulatory Submissions in Electronic Format –

3 General Considerations

4

5

6

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

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

9 bind FDA or the public. You can use an alternative approach if it satisfies the requirements of the

10 applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff

11 responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the

12 appropriate number listed on the title page of this guidance.

13

14

15

16

17 I. INTRODUCTION

18

19 This is one in a series of guidance documents intended to assist you when making regulatory

20 submissions in electronic format to the Food and Drug Administration (FDA). This guidance

21 discusses general issues common to all types of electronic regulatory submissions. This is a

22 revision to the guidance of the same name that issued in January 1999. Once it has been

23 finalized, this guidance will replace the January 1999 guidance. 

24

25 This guidance is being revised to address electronic submissions coming into all centers of the

26 Agency. Changes from the 1999 version of the guidance also include addition of a new section

27 describing the relationship of electronic submissions to 21 CFR part 11. There are updates on the

28 recommendations for creating PDF documents including specific guidance for the use of fonts.

29 New file formats for data, specifically XML and SGML are introduced. The electronic

30 transmission of files is discussed. In some cases, the guidance for one center differs some from

31 that of another center because of differences in procedures and in the computer infrastructures in

32 the centers. We will work to minimize these differences wherever possible. 

33

34 Agency guidance documents on electronic regulatory submissions will be updated regularly to

35 reflect the evolving nature of the technology involved and the experience of those using this

36 technology. 

37

38 FDA's guidance documents, including this guidance, do not establish legally enforceable

39 responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should

40 be viewed only as recommendations, unless specific regulatory or statutory requirements are

 

1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) in cooperation with the

Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), Center

for Food Safety and Applied Nutrition (CFSAN), and Center for Veterinary Medicine (CVM) at the Food and Drug

Administration. 
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41 cited. The use of the word should in Agency guidances means that something is suggested or

42 recommended, but not required.

43

44

45 II. BACKGROUND

46

47 In the Federal Register of March 20, 1997 (62 FR 13430), the FDA published the Electronic

48 Records; Electronic Signatures regulation (21 CFR part 11). This regulation provides, among

49 other things, for the voluntary submission of parts or all of records in electronic format without

50 an accompanying paper copy under certain circumstances. In January 1999, the Center for

51 Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research

52 (CDER) finalized a joint guidance document on general considerations for electronic

53 submissions. They also published guidance documents describing how to provide marketing

54 applications to each center. Following publication of these guidance documents, a working

55 group was formed with the CBER, CDER, Center for Devices and Radiological Health (CDRH),

56 the Center for Food Safety and Applied Nutrition (CFSAN), and the Center for Veterinary

57 Medicine (CVM) to coordinate electronic submission activity. The efforts of this working group

58 have resulted in this draft guidance, which updates the 1999 general considerations guidance

59 document. 

60

61 The Agency envisions a series of guidance documents on electronic regulatory submissions. As

62 individual documents are completed, they will be issued first in draft for comment, then finalized

63 and added to the series. The guidances will be updated regularly to reflect the continuously

64 evolving nature of the technology and experience of those using this technology.

65

66

67 III. HOW DO ELECTRONIC SUBMISSIONS RELATE TO 21 CFR PART 11?

68

69 FDA's part 11 regulations (21 CFR part 11), among other things, set forth the criteria under

70 which records submitted to FDA may be submitted in electronic format in place of paper.

71 Section 11.2(b) states that, for records submitted to the Agency, persons may use electronic

72 records in lieu of paper records, in whole or part, provided the requirements of part 11 are met

73 and the documents or parts of documents to be submitted have been identified by the Agency in

74 public docket No. 92S-0251 as being the type of submission the Agency is prepared to accept in

electronic format.2 75 

76

77

78 IV. WHAT FILE FORMATS SHOULD I USE FOR ELECTRONIC DOCUMENTS? 

79

80 Documents submitted in electronic format should:

81

82 • Enable the user to easily view a clear and legible copy of the information 

83

 

2 For a discussion of the Agency's perspectives on 21 CFR part 11, see the guidance for industry Part 11, Electronic

Records; Electronic Signatures — Scope and Application, which issued in September 2003.
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84 • Enable the user to print each document page by page, as it would have been

85 provided in paper, maintaining fonts, special orientations, table formats, and page

86 numbers

87

88 • Include a well-structured table of contents and allow the user to navigate easily

89 through the submission 

90

91 • Allow the user to copy text, images and data electronically into other common

92 software formats.

93

94 To achieve the above goals, you should submit all electronic documents in portable document

95 format (PDF). We are prepared to archive documents provided as PDF files. PDF is an open,

96 published format created by Adobe Systems Incorporated (http://www.adobe.com). You do not

97 need to use a product from Adobe or from any specific company to produce your PDF

98 documents. PDF has been accepted as a standard for providing documents in electronic format

99 by the International Conference on Harmonisation (ICH). 

100

101 The following will help you create PDF files that we can review and archive. 

102

103 A. Version

104

105 We should be able to read all PDF files with Acrobat Reader version 4.0, and above, with

106 the search plug in. We should not need any additional software to read and navigate the

107 PDF files. 

108

109 B. Fonts

110

111 PDF viewing software automatically substitutes a font to display text if the font used to

112 create the text is unavailable on the reviewer’s computer. In some cases, font substitution

113 can occur even when the fonts are available. For example, Helvetica or Times are

114 substituted even if available on the reviewer’s computer. Font substitution can affect a

115 document’s appearance and structure, and in some cases it can affect the information

116 conveyed by a document. We cannot guarantee the availability of any one font.

117 Therefore, you should embed all fonts you are using in the PDF files to ensure that those

118 fonts will always be available to the reviewer. When embedding fonts, all characters for

119 the font should be embedded, not just a subset of the fonts being used in the document.

120

121 However, font embedding does not solve the problems that occur when a reviewer tries to

122 paste text from a PDF document into another software format. If the font is not available

123 on the reviewer’s computer, font substitution results even if the fonts are embedded. For

124 this reason, we ask that you restrict the fonts used in documents to one of the following

125 fonts listed in Table 1. We still ask that you embed the fonts so they are available for

126 printing older archival files. 

127
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128 Table 1: List of recommended fonts

Font type Font name

San Serif AdobeSansMM (Adobe Sans Multiple Master)

Arial BolitaMT (Arial Bold Italic (From Monotype))

ArialBolMT (Arial Bold Monotype)

ArialtaMT Arial Italic (Monotype)

ArialMT Arial (Monotype)

Non proportional Couri (Courier)

CouriBol (Courier Bold)

CourriBolObl (Courier Bold Oblique)

Serif AdobeSerifMM (Adobe Serif Multiple Masters)

TimesNewRomPSBolitaMT (Times New Roman Bold

Italic)

TimesNewRomPSBolMT (Times New Roman Bold)

TimesNewRomPSItaMT (Times New Roman Italic)

TimesNewRomPSMT (Times New Roman)

TimesNewRoman

Other Symbo (Symbol)

ZapfDin (Zapf Dingbats)

129

130

131 Resizing a submitted document because the contents are too small to read is inefficient.

132 We believe that Times New Roman, 11 or 12-point font (the font used for this

133 document), is adequate in size for reading narrative text. When making point size larger,

134 data comparisons could become problematic because data that normally might appear in

135 one table would now appear in multiple tables. When choosing a point size for tables, a

136 balance should be made between providing sufficient information on a single page that

137 may facilitate data comparisons while still achieving a point size that remains legible.

138 Generally, point sizes 9-10 are recommended for tables; smaller point sizes should be

139 avoided. Ten point fonts are recommended for footnotes. 

140

141 We recommend the use of a black font color. Blue font can be used for hypertext links

(preferred for submissions to CBER3 142 and CFSAN). If a font color other than black is

143 used, you should avoid light colors that do not print well on grayscale printers. You can

144 test the color reproduction prior to submission by printing sample pages from the

145 document using a grayscale printer.

146

147 C. Page Orientation 

148

 

3 The Commissioner has announced a consolidation of the CDER/CBER review functions for therapeutic products.

Once the consolidation has been completed, we will review those guidances that have been affected by the transfer

of functions for possible revision.
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149 Pages should be properly oriented to reduce the effort of rotating pages. For example,

150 you should set the page orientation of landscape pages to landscape prior to saving the

151 PDF document in final form to ensure correct page presentation.

152

153 D. Page Size and Margins

154

155 The print area for pages should fit on a sheet of paper that is 8.5 inches by 11 inches.

156 You should allow a margin of at least 1 inch on the left side of page (to avoid obscuring

157 information when the pages are subsequently printed and bound) and 3/8 of an inch on

158 the other sides. For pages in landscape orientation, you should allow 3/4 of an inch at the

159 top to allow more information to be displayed legibly on the page. Header and footer

160 information can appear within these margins as long as it is not within 3/8 of an inch of

161 the edge of the 8.5 by 11 inch page, because the text may be lost upon printing or being

162 bound.

163

164 E. Source of Electronic Document

165

166 PDF documents produced by scanning paper documents are usually inferior to those

167 produced from an electronic source document. Scanned documents are more difficult to

168 read and do not allow us to search or copy and paste text for editing in other documents.

169 They should be avoided if at all possible. If you use optical character recognition

170 software, you should verify that all imaged text converted by the software is accurate. 

171

172 F. Methods for Creating PDF Documents and Images

173

174 You should choose a method for creating PDF documents that produces the best

175 replication of a paper document. You can ensure that the paper and PDF version of the

176 document are the same by printing the document from the PDF version.

177

178 Documents that are available only in paper should be scanned at resolutions that will

179 ensure the pages are legible both on the computer screen and when printed. At the same

180 time, you should also limit the file size. We recommend scanning at a resolution of 300

181 dots per inch (dpi) to balance legibility and file size. We discourage the use of grayscale

182 or color because of file size. But, if you believe their use is necessary, the following

183 paragraphs provide preliminary recommendations, and specific guidance documents

184 provide additional details. After scanning, you should avoid resampling to a lower

185 resolution. 

186

187 The optimal image resolution and bit depth depends to a large part on the actual need for

188 viewing the image. You should not provide images at high resolution and depth without

189 determining the need. High resolution and depth images result in large files, taking up

190 valuable storage space. It is better to provide samples to the appropriate center of the

191 images at various resolutions and depths prior to sending in the actual submissions to

192 determine the optimal image resolution and depth to meet the review need.

193
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194 When creating PDF files containing images, you should not resample images.

195 Resampling does not preserve all of the pixels in the original. For PDF images, you can

196 use one of the following lossless compression techniques. 

197

198 • For lossless compression of color and grayscale images, you should use Zip/Flate

199 (one technique with two names). This is specified in Internet RFC 1950 and RFC

200 1951 (http://info.internet.isi.edu/in-notes/rfc/files/rfc1950.txt). 

201

202 • For lossless compression of black and white images, you should use the CCITT

203 Group 4 Faxcompression technique. It is specified as CCITT recommendations

204 T.6 (1988) - Facsimile coding schemes and coding control functions for Group 4

205 facsimile apparatus. 

206

207 When submitting medical images to CBER, such as X-ray, CT, ultra sound, PET, and

208 SPECT, they should not be compressed. 

209

210 Note: if you use lossless compression, there should not be a change in the label size and

211 format.

212

213 Paper documents containing handwritten notes should be scanned at 300 dpi.

214 Handwritten notes should be done in black ink for clarity.

215

216 For photographs, the image should be obtained with a resolution of 600 dpi. If black and

217 white photos are submitted, consider 8-bit gray scale images. If color photos are

218 submitted, consider 24-bit RGB images. A captured image should not be subjected to

219 nonuniform scaling (i.e., sizing). 

220

221 Gels and karyotypes should be scanned directly, rather than from photographs. Scanning

222 should be at 600 dpi and 8-bit grayscale depth. 

223

224 Plotter output graphics should be scanned or captured digitally at 300 dpi. 

225

226 High-pressure liquid chromatography or similar images should be scanned at 300 dpi. 

227

228 When color is important in the review of a file, labeling for example, you should make

229 sure that the colors are an accurate representation of the actual image. Since color varies

230 from monitor to monitor, it is difficult to ensure that the reviewer will see exactly the

231 same color as in the actual image. However, for printing, there is more control over the

232 color if you use CMYK color model as opposed to the RGB model. Since PDF uses the

233 color profile provided by CMYK, you can use Pantone Matching and this will ensure

234 color consistency for printing. PDF also uses the ICC color profile specifications when

235 PDF documents are printed.

236

237 G. Hypertext Linking and Bookmarks

238
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239 Hypertext links and bookmarks are techniques used to improve navigation through PDF

240 documents. Hypertext links can be designated by rectangles using thin lines or by blue

241 text (the latter is preferred by CBER and CFSAN). We recommend you use invisible

242 rectangles for hypertext links in a table of contents to avoid obscuring text.

243 Recommendations for hypertext linking and bookmarks are provided in the guidance for

244 the specific submission type. 

245

246 In general, for documents with a table of contents, you should provide bookmarks and

247 hypertext links for each item listed in the table of contents including all tables, figures,

248 publications, other references, and appendices. These bookmarks and hypertext links are

249 essential for the efficient navigation through documents. Bookmarks to the roadmap

250 (when applicable), main table of contents, and item table of contents for the section of the

251 application a reviewer has accessed, at the top of the bookmark hierarchy, are extremely

252 helpful. The bookmark hierarchy should be identical to the table of contents with

253 exceptions made for the following three bookmarks – the roadmap (when applicable), the

254 main table of contents, and the item table of contents being accessed by a reviewer. You

255 should avoid using bookmark levels in addition to those present in the table of contents.

256 Each additional level increases the need for space to read the bookmarks. We

257 recommend using no more than 4 levels in the hierarchy. 

258

259 Hypertext links throughout the body of the document to supporting annotations, related

260 sections, references, appendices, tables, or figures that are not located on the same page

261 are helpful and these hypertext links improve navigation efficiency. You should use

262 relative paths when creating hypertext linking to minimize the loss of hyperlink

263 functionality when folders are moved between disk drives. Absolute links that reference

264 specific drives and root directories will no longer work once the submission is loaded

265 onto our network servers. 

266

267 When creating bookmarks and hyperlinks, you should choose the magnification setting

268 Inherit Zoom so that the destination page displays at the same magnification level that the

269 reviewer is using for the rest of the document.

270

271 H. Page Numbering

272

273 See guidance for the specific submission type for guidance on page numbering.

274

275 In general, it is easier to navigate through an electronic document if the page numbers for

276 the document and the PDF file are the same. The initial page of the document should be

277 numbered as page one, with two exceptions. One, when a document is split because of

278 its size (e.g., > 50 MB), the second or subsequent file should be numbered consecutively

279 to that of the first or preceding file. Two, when several small documents with their own

280 internal page numberings have been brought together into a single file, it is not necessary

281 to renumber the documents into one page sequence, although you should provide a

282 bookmark at the start of each subdocument. For example, if you are adding an original

283 protocol as an appendix to a study report, you should not add page numbers to the
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284 original protocol so the page numbers are consecutive to the rest of the study report. You

285 should provide a bookmark to the original protocol.

286

287 I. Document Information Fields

288

289 Document information fields are used to search for individual documents and to identify

290 the document when found. Recommendations for the document information fields will

291 be provided in the guidance for the specific submission type.

292

293 J. Open Dialog Box

294

295 The open dialog box sets the document view when the file is opened. The initial view of

296 the PDF files should be set as Bookmarks and Page. If there are no bookmarks, we

297 recommend that you set the initial view as Page only. You should set the Magnification

298 and Page Layout to default.

299

300 K. Naming PDF Files

301

302 Recommendations on names to use for folders and selected files are provided in the

303 individual guidances for specific submission types. For uniformity, you should use our

304 specific naming conventions when they are provided. Reviewers are trained to look for

305 these folders and files, and using the recommended names should help avoid

306 misunderstandings, improve communication, and speed the review of a submission. 

307

308 When we do not specify a file name, you can use file names up to 32 characters in length

309 including PDF as the 3-character extension. We recommend that you avoid using

310 punctuation, dashes, spaces, or other nonalphanumeric symbols (e.g., \ / : * ? < > | “ % #

311 +) in file names. Underlines can be used.

312

313 L. Security

314

315 You should not include any security settings or password protection for PDF files except

316 when recommended in guidance for a specific submission type. You should allow

317 printing, changes to the document, selecting text and graphics, and adding or changing

318 notes and form fields. Our internal security and archival processes will maintain the

319 integrity of the submitted files. A read-only copy of the files, generated from the

320 submitted files, will be provided to the reviewer.

321

322 M. Indexing PDF Documents

323

324 We use full text indexes to help find specific documents and/or search for text within

325 documents. When a document or group of documents is indexed, all words and numbers

326 in the file and all information stored in the document information fields are stored in

327 special index files that are functionally accessible using the search tools available in

328 Acrobat. Portions of a document that are imaged are not indexed. Even if the document
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329 only contains images, the text in the Document Information fields of the file will be

330 indexed. 

331

332 These full text indexes should not be confused with a table of contents. Adobe Acrobat

333 Catalog is one example of a tool that can be used to index PDF documents. Indexes

334 should not require extensions or additions to the off-the-shelf Acrobat Reader.

335

336 With many submissions, we ask that you associate the table of contents file for a section

337 with the corresponding full text index file. By associate, we mean that when the table of

338 contents file is opened, the index file is automatically added to the available index list and

339 is ready to be used. 

340

341 Further recommendations for full text indexes will be provided in individual guidances

342 for the specific submission types.

343

344 N. Plug Ins

345

346 You can use plug ins to assist in the creation of a submission. However, the review of the

347 submission should not require the use of any plug ins, in addition to those provided with

348 the latest Acrobat Reader because we are not prepared to archive additional plug-in

349 functionality.

350

351

352 V. WHAT FILE FORMATS SHOULD I USE FOR ELECTRONIC DATASETS?

353

354 You should provide data subsets in certain formats. Currently, we are able to accept and archive

355 datasets in SAS System XPORT transport format (Version 5 SAS transport file). In

356 circumstances when data are moved directly to a database or special review tool, tagged ASCII

357 file, specifically, standard generalized markup language (SGML) and extensible markup

358 language (XML), may be the appropriate file format. At times, delimited ASCII files are also

359 acceptable. See the individual guidance for the specific submission type for the appropriate

360 dataset format. 

361

362 A. SAS System XPORT Transport Format (Version 5 SAS Transport Format)

363

364 SAS XPORT transport format, also called Version 5 SAS transport format, is an open

365 format published by the SAS Institute. The description of this SAS transport file format is

366 in the public domain. Data can be translated to and from this SAS transport format to

367 other commonly used formats without the use of programs from SAS Institute or any

368 specific vendor. 

369

370 You should follow the recommendations in this section to create SAS transport files that

371 we can review and archive. 

372
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373 1. Version

374

375 In SAS, SAS XPORT transport files are created by PROC XCOPY in Version 5

376 of SAS software and by the XPORT engine in Version 6 and higher of SAS

377 Software. We are unable to archive SAS Transport files processed by the CPORT

378 engine.

379

380 You can find the record layout for SAS XPORT transport files in SAS technical

381 support TS-140. This document and additional information about the SAS

382 Transport file layout can be found on the SAS World Wide Web page at

383 http://www.sas.com/fda-esub.

384

385 2. Transformation of Datasets

386

387 We use a variety of software tools to analyze the datasets. Stat/Transfer from

388 Circle Systems and DBMS/copy from Conceptual Software Inc., are two

389 programs used to convert data to various formats used for analysis. SAS Viewer

390 version 7 or higher is used to open SAS transport files directly.

391

392 3. Naming SAS Transport Files

393

394 All SAS transport files should use xpt as the file extension.

395

396 4. Compression of SAS Transport Files

397

398 SAS transport files should not be compressed. There should be one transport file

399 per dataset.

400

401 5. Content of Datasets and Organization

402

403 You should provide a single transport file for each dataset. Many of the software

404 tools used by the reviewers require datasets to be loaded into random access

405 memory (RAM) prior to opening the file. Therefore, dataset files should be

406 organized so that their size is generally less than 50 MB per file. Datasets divided

407 to meet the maximum size restrictions should contain the same variable

408 presentation so they can be easily merged, joined, and concatenated. The datasets

409 should be accompanied by data definition tables that include metadata such as the

410 variable name, a description of the variable, the type of variable (e.g., number,

411 character, date), and codes used in the dataset. Variable names should be limited

412 to 8 characters. You should include a descriptive name up to 40 characters in the

413 label header. Further recommendations for content of SAS Transport files are

414 provided in guidance for each specific submission type. 

415

416 We recommend that you discuss the content of the datasets with the review

417 division prior to submission. 
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418

419 B. XML

420

421 Extensible markup language (XML) was developed by a working group at the World

422 Wide Web Consortium (W3C). It is a nonproprietary language developed to improve on

423 previous mark up languages including standard generalized markup language (SGML)

424 and hypertext markup language (HTML). XML is not as complicated to use as SGML

425 and is more flexible than HTML. 

426

427 Information in an XML file is divided into specific pieces. These pieces are called objects

428 or elements types. The element type identifies the piece of information. For example, the 

429 NDA application number might be identified with the element type <appNum>. All 

430 element type names are bracketed using the special characters < >. Inside the XML

431 document, the element type name is placed just prior to the piece of information and after

432 the information. This is called tagging. So, in the XML file, the application number for 

433 NDA 123456 would be tagged as follows <appNum>123456</appNum>. The / prior to

434 the element type denotes that this is the end of the information about the appNum. 

435

436 By using a hierarchial structure, XML allows you to relate two or more elements. This is

437 accomplished by nesting one element within another.

438

439 Additional information about the element type is provided by attributes. Attributes are

440 placed within the element types and are surrounded by “ ”. For example, if you wanted

441 to identify the type of the application number as an NDA, you could add this piece of

442 information as an attribute. This could be represented in the XML file as <appNum

443 type=”NDA”>123456</appNum>. 

444

445 Internet browsers read XML files. Style sheets provide the browser with the information

446 necessary to create tables, fonts, and colors for display in the XML file. 

447

448 The specific names of the element types and attributes as well as the valid syntax,

449 structure and format for defining the XML elements are included in a file called

450 document type declaration (DTD). If the XML document does not follow the DTD, the

451 file might not be used properly. 

452

453 We currently use XML version 1.0 recommended by the World Wide Web Consortium

454 (W3C). We will be evaluating additional uses for XML as enhancements for data

455 exchange evolve and extensions are developed. Additional information can be found at

456 the W3C web site at www.w3c.org.

457

458 For specific tags and formats see the individual guidance document for the specific

459 submission type. 

460

461 C. SGML

462
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463 A working group at the W3C developed standard generalized markup language (SGML).

464 It is a nonproprietary language developed to organize and transmit information in digital

465 format. It shares many of the features of XML described above. Additional information

466 can be found at the W3C web site at www.w3c.org. 

467

468 D. Molfiles

469

470 The file format called Molfile is in the public domain and was developed by Molecular

471 Design Limited (MDL) in the late 1970’s. Currently, the company, now named

472 Molecular Design Limited Information Systems, is a wholly owned subsidiary of Elsevier

473 Science. Technical information about the Molfile format can be found at the MDL web

474 site at http://www.mdli.com/downloads/literature/ctfile.pdf.

475

476 Molfiles are generated by chemical structure drawing programs. The most common

477 drawing programs, ISIS/Draw from MDL and ChemDraw Pro from Cambridge Soft

478 (http://www.cambridgesoft.com), create Molfiles. A free copy of ISIS/DRAW for your

479 personal use may be obtained from the MDL Web site at

480 http://www.mdli.com/downloads/isisdraw.html.

481

482 Molfiles can be viewed and reformatted using Chime, a free plug in to Microsoft

483 Internet Explorer and Netscape Communicator from MDL. You can download the plug

484 in at http://www.mdli.com/downloads/chime.html.

485

486 Molfiles can be searched using database programs such as ISIS Base. Additional

487 Information about this database program can be found at the MDL web site at

488 http://www.mdli.com.

489

490

491 VI. WHAT ARE THE PROCEDURES FOR SENDING ELECTRONIC

492 SUBMISSIONS FOR ARCHIVE?

493

494 Electronic submissions should be provided in electronic format, either on physical media or by

495 acceptable methods of electronic transport. You should refer to the individual guidance for the

496 specific submission type for the appropriate procedures to use for sending electronic submissions

497 for archive.

498

499 A. Electronic Transmission

500

501 Currently, we have identified three methods for sending submissions electronically.

502 Submissions using electronic data interchange (EDI), web-based transmissions, and

503 secure email. We will provide additional information on these transmission methods as

504 they are used for specific submission types. For example, CVM accepts electronic

505 submission of certain types by attaching encrypted PDF files to e-mail to the Electronic

506 Document Control Unit at cvmdcu@cvm.fda.gov. You can get more information at

507 www.fda.gov/cvm/fda/TOCs/guideline.html.
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508

509 B. Physical Media

510

511 The following information is important when sending electronic submissions on physical

512 media. See Appendix A: Additional information on providing Electronic Submissions

513 on Physical Media for additional information.

514

515 1. Where do I send the electronic submission?

516

517 Electronic submissions should be sent directly to the appropriate center involved. See

518 guidance for specific submission type for additional information. 

519

520 • CBER

521

522 You should provide a minimum of two copies of the submission. One copy will be

523 used to load the submission into our electronic document room (EDR). This copy

524 will be made available to the Agency's review community upon request. The second

525 copy will be archived for disaster recovery. Additional copies of items of an

526 application, bundled by review discipline, may be requested to facilitate the review

527 offsite. All materials are received centrally within CBER and should be addressed as

528 follows:

529

530 Center for Biologics Evaluation and Research

531 Document Control Center, HFM-99

532 Food and Drug Administration

533 1401 Rockville Pike 

534 Rockville, MD 20852-1448

535

536 Submitting organizations should use the above address for regulatory documents and

537 media in support of applications within CBER. This includes regulatory documents and

538 media sent via U.S. Postal Service or via common or private carriers.

539

540 • CDER

541

542 Unless otherwise specified in the specific submission guidance, send one copy of the

543 electronic regulatory submission for archive to the CDER Central Document Room.

544

545 • CDRH

546

547 Contact the appropriate reviewing division prior to making an electronic submission.

548 The division will inform you as to where and how to send submissions. Contacts can be

549 found at http://www.fda.gov/cdrh/organize.html#ODE. See individual guidance for

550 specific submission type for additional information.
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551

552 • CFSAN

553

554 CFSAN’s Office of Nutritional Products, Labeling, and Dietary Supplements (ONPLDS)

555 is working on procedures for submitting new dietary ingredient notifications and

556 applications for temporary marketing permits. Unless otherwise specified in the specific

557 submission guidance, send one copy of the electronic regulatory submission for ONPLDS

558 to the following address:

559

560 Office of Nutritional Products, Labeling, and Dietary Supplements

561 Center for Food Safety and Applied Nutrition

562 5100 Paint Branch Parkway, HFS-800

563 College Park, MD 20740

564

565

566 Currently, CFSAN’s Office of Food Additive Safety (OFAS) accepts a submission

567 provided only on physical media. All submissions should be sent directly to OFAS. The

568 procedure for handling paper submissions is unchanged from the past.

569

570 You should send electronic and paper submissions to:

571

572 Office of Food Additive Safety

573 Center for Food Safety and Applied Nutrition

574 Food and Drug Administration

575 5100 Paint Branch Parkway

576 College Park, MD 20740

577

578 You should communicate with OFAS prior to submitting an electronic document,

579 notifying it of your intention to submit an electronic document in advance of the target

580 date for the submission

581

582 OFAS will schedule a teleconference or meeting between petitioners and the appropriate

583 OFAS staff. The objective of the teleconference is to convey information relating to the

584 proposed electronic submission’s management paradigm, content, format, and structure.

585 Moreover, OFAS will discuss any issues specific to your submission that may not have

586 been fully addressed in this general considerations guidance. The amount of time that

587 will be needed to ensure that the document is ready for submission will depend on the

588 complexity of the document and experience of the said submitter in preparing petitions

589 and notifications.

590

591 • CVM

592

593 We are working on procedures for accepting electronic submissions on physical media.

594 See individual guidance for specific submission type for additional information.

595
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596 2. What type of media should I use?

597

598 We are prepared to accept electronic submissions on CD-ROM and digital tape. In

599 CDER and CFSAN, you can also use floppy disks. To optimize processing efficiency,

600 we recommend choosing media with a capacity most appropriate to the size of the

601 submission. Whenever possible, applicants should choose media capable of holding the

602 submission on the fewest number of units.

603

Recommendations for Media

Size of Submission Media and format Units 

Less than 10MB* 3.5 inch DOS Formatted Floppy Disks 1 to 10 

Less than 3.25GB CD-ROM ISO 9660 1 to 5 CDs 

Greater than 3.25GB Digital Linear Tape (DLT) 35/70, 20/40 and

10/20 GB format using NT server 4.0 with

NT backup or backup exec.

No limit

604 *This is not an option for CBER and CVM

605

606 3. How should I prepare the media for electronic submissions?

607

608 You should send all electronic media adequately secured in a standard binder marked

609 clearly on the outside ELECTRONIC REGULATORY SUBMISSION FOR ARCHIVE.

610 CDs should be packaged carefully to ensure that they arrive in a usable condition.

611 Particularly vulnerable are diskettes and CD jewel cases shipped in envelopes without

612 bubble-type protective material or stiff backing. We do not recommend the use of jiffy613 type bags alone to ship media because they may not provide adequate protection. 

614

615 You should provide the following identification information on the media, as appropriate:

616

617 • Sponsor, applicant or company name

618 • Name of the product, chemical, or ingredient

619 • Appropriate regulatory ID number (e.g., Petition Notification number, NDA,

620 IND, BLA number, petition or notification number)

621 • Application type (e.g., IND amendment, BLA supplement, title of petition or

622 notification)

623 • Submission date in the format of dd-mmm-yyyy

624 • Copy number (e.g., original, copy 1, copy 2)

625 • Media series (e.g., “1 of 1,” "1 of 2”)

626 • When sending CD-ROMs to OFAS, number them from 0.001 through 0.XXX

627 for the original submission, and 1.001 through 1.XXX for subsequent

628 submissions to the same files with additional information.

629

630

631 You should include the information directly on the DLT tape cover label. For CDROMs,

632 you should include the information on the jewel case. The CDROM itself should include,
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633 at a minimum, sufficient identification information so that it can be paired with the jewel

634 case bearing the complete identification information, in the event that they become

635 separated. See the individual guidance for the specific submission type for additional

636 information on labeling physical media.

637

638

639 VII. WHAT IF I HAVE A QUESTION?

640

641 A. CBER

642

643 You can submit questions pertaining to the preparation of submissions, in electronic

644 format, for CBER to ESUBPREP@CBER.fda.gov. 

645

646 B. CDER

647

648 We maintain a web site on electronic submissions at

649 www.fda.gov/cder/regulatory/ersr/default.htm. You can direct questions regarding the

650 preparation of submissions in electronic format in CDER to esub@cder.fda.gov. 

651

652 C. CDRH

653

654 You can submit questions about electronic submissions via email to esub@cdrh.fda.gov.

655 We also maintain a web site on electronic submissions at

656 www.fda.gov/cdrh/elecsub.html. In addition, you can sign up for email updates on the

657 CDRH home page at www.fda.gov/cdrh. 

658

659 D. CFSAN

660

661 You can direct questions regarding the preparation of submissions in electronic format in

662 CFSAN to the Electronic Submissions Coordinator email esubprep@opa.fda.gov. 

663

664 E. CVM

665

666 You can direct questions regarding the preparation of submissions in electronic format in

667 CVM to the Electronic Submissions Coordinator, email cvmstars@cvm.fda.gov or you

668 can call the Center Hot Line at 301-827-8277. Additional information on electronic

669 submissions can be found at http://www.fda.gov/cvm/guidance/guidance.html.

670

671
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672

673 APPENDIX A: ADDITIONAL INFORMATION ON PROVIDING ELECTRONIC

674 SUBMISSIONS ON PHYSICAL MEDIA

675

676 CBER

677

678 Processing the electronic submission

679

680 The structure and content of electronic submissions to CBER should be based upon the

681 application (e.g., BLA and IND). Subsequent to the delivery of an electronic

682 application, any additional electronic information (i.e., amendments) will be added to

683 the existing copy of the submission residing in the Electronic Document Room (EDR).

684 BLA supplements are treated as separate submissions, not as continuations of the base

685 application. They will be stored in their own EDR folder. The root directory of an

686 electronic application should contain a roadmap.pdf file to orient the review team to the

687 application as well as subsequent information amending the application.

688 Roadmap file

689

690 CBER suggests that a roadmap.pdf file be used to establish hypertext links to an

691 application's or amendment's main table of contents and to the application folders and

692 files. If an application is submitted on multiple CDROMs or DLT tapes, each unit of

693 media should contain the identical roadmap.pdf file, which links to folders and files on

694 all of the media units. This roadmap file should be updated and resubmitted when

695 additional information is submitted to amend an application.

696 The roadmap.pdf file should be placed in the root directory of a submission. This

697 ensures that the outdated roadmap.pdf file is overwritten each time a new amendment is

698 loaded into the EDR. The roadmap file should not contribute in any way to the content

699 of the submission under review. It is a map, intended to facilitate navigation through the

700 contents of an application. The application's roadmap.pdf file should be easily updated

701 or modified, for example, using the Replace File command under the Document menu

702 option in Adobe Exchange. This function will automatically replace the old hypertext

703 links to previously submitted sections of the application, leaving only the task of creating

704 the new links corresponding to newly submitted information.

705 In addition to providing a navigable guide to the application, the roadmap.pdf file should

706 include the sponsor’s submission date in the DD-MMM-YYYY format (e.g., 01-Jan707 1999). The contents of the original application and any subsequent amendments to that

708 application should be briefly described in a roadmap.pdf table. The location of these

709 files and folders on the submitted media should be indicated in the roadmap.pdf. Where

710 portions of an application have been submitted only as a paper documents, they should

711 be included in the roadmap and table of contents and tagged as paper only.

712

713 The following text is a representative example of a roadmap.pdf file.
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714

715 Electronic Roadmap

716

717 BLA Submission Submission Date Submission Content CD-ROM Hypertext link Destination 

718

719 Sponsor Name 15-Jan-1999 FDA Form 356h .001 ../blatoc.pdf

720 cover.pdf .001

721 BLA Table of Contents .001

722 Item 01-Index .001

723 Item 02-Labeling .001

724 Item 03-Summary .001

725 Item 04-CMC .001

726 Item 05-Pharmtox .001

727 Item 06-Cpbio .001

728 Item 08-Clinical .002

729 Item 10-Statistical .002

730 Item 12-Crf .002

731 Item 15-Estab .002

732 Others (Items 13-16) .002

733

734 BLA 123456/5001/1 01-Apr-1999 cover.pdf` .001 ..\ 123456/5001/1\ amendtoc.pdf

735 confid.pdf .001

736 CMC .001

737

738 BLA 123456/5001/2 19-Jun-1999 Cover.pdf .001 ..\ 123456/5001/2\amendtoc.pdf

739 Clinstat .001

740

741 BLA 123456/5001/3 04-Jul-1999 cover.pdf .001 ..\ 123456/5001/3 \amendtoc.pdf

742 confid.pdf .001

743 Clinstat .001

744 Safety Update .001

745

746

747 Summary File

748

749 A summation of the electronic document, using at least 40 key words from the

750 main document, should be included with all electronic applications delivered to

751 CBER. This summation should be located in the root directory on the

752 CDROM or DLT tape. The file containing the key words should be an ASCII

753 text file entitled Summary.txt.

754

755 CDER

756

757 In general, when an electronic submission arrives in CDER, we copy the electronic files

758 to tape to create an archival copy of the submission. We also copy the files to a network

759 server to create a read-only copy for the reviewer. See specific submission type guidance

760 for additional details. 

761
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762 CDRH

763

764 Contact the appropriate reviewing division prior to making an electronic submission.

765 The division will inform you as to where and how to send submissions. Contacts can be

766 found at http://www.fda.gov/cdrh/organize.html#ODE. See individual guidance for

767 specific submission type for additional information.

768

769 CFSAN

770

771 When an electronic submission arrives in OFAS one copy of the media is archived: the

772 second copy of the submission’s media is copied to a network server to create a read-only

773 copy for the reviewer.

774

775 The structure and content of electronic submissions to OFAS should be based upon the

776 application (e.g., Petition, Notification). Subsequent to the delivery of the electronic

777 application, any additional electronic and/or paper information will be added to the

778 existing network copy of the submission and made available to appropriate managers and

779 reviewers. The root directory of an electronic application should contain a roadmap.pdf

780 file to orient the review team to the original application and to any and all subsequent

781 information added to the application.

782

783 OFAS suggests that a roadmap.pdf file be used to establish hypertext links to the

784 application’s main table of contents and to the application folders and files. This

785 roadmap or home page should be updated and resubmitted as additional information to

786 the application.

787

788 The roadmap file should not contribute in any way to the content of what is under review.

789 It is a map, intended to facilitate navigation through the contents of an application. The

790 application's roadmap.pdf file should be easily updated or modified, for example, using

791 the Replace File command under the Document menu option in Adobe Exchange. This

792 function will automatically replace the old hypertext links to previously submitted

793 sections of the application, leaving only the task of creating the new links corresponding

794 to newly submitted information. 

795

796 In addition to providing a navigable guide to the application, the roadmap.pdf file should

797 include the sponsor’s submission date in the DD-MMM-YYYY format.17 (e.g., 01-Jan798 2000). The contents of the original application and any subsequent amendments to that

799 application should be briefly described in a roadmap.pdf table. The location of these files

800 and folders on the submitted media should be indicated in the roadmap.pdf. Where

801 portions of an application have been submitted only as paper documents, they should be

802 included in the roadmap and table of contents and tagged as paper only.

803

804 A summation of the electronic document, using at least 40 key words from the main

805 document should be included with all electronic applications delivered to OFAS. This
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806 summation should be located in the root directory on the CDROM or DLT tape. The file

807 containing the key words should be an ASCII text file entitled Summary.txt.

808

809 CVM

810

811 We are developing procedures for processing electronic submissions sent on physical

812 media. See individual guidance for specific submission type for additional information.