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Guidance for Industry
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Providing Regulatory Submissions in 
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Electronic Format   
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Orphan-Drug and  
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Humanitarian Use Device Designation 
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Requests and Related Submissions  
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DRAFT GUIDANCE
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14    This guidance document is being distributed for comment purposes only. 
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16  Comments and suggestions regarding this draft document should be submitted within 60 days of 
17  publication in the Federal Register of the notice announcing the availability of the draft 
18  guidance.  Submit comments to Dockets Management Branch (HFA-305), Food and Drug 
19  Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD  20852.  All comments should be 
20  identified with the docket number listed in the notice of availability that publishes in the Federal 
21  Register. 
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23  For questions regarding this draft document send an e-mail to james.bona@fda.hhs.gov 
24  or contact James D. Bona, 301-827-0978. 
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32  U.S. Department of Health and Human Services 
33  Food and Drug Administration 
34  Office of Orphan Products Development (OPD) 
35  February 2006 
36  Electronic Submissions 
    Draft-Not for Implementation 
 
Guidance for Industry
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Providing Regulatory Submissions in 
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Electronic Format   
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Orphan-Drug and  
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Humanitarian Use Device Designation 
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Requests and Related Submissions  
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48  Additional copies are available at: 
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50  http://www.fda.gov/orphan/esub/esub.htm 
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69  U.S. Department of Health and Human Services 
70  Food and Drug Administration 
71  Office of Orphan Products Development (OPD) 
72  February 2006 
73  Electronic Submissions 
  Contains Nonbinding Recommendations
 
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74  TABLE OF CONTENTS 
75  I.  INTRODUCTION.............................................................................................................1 
76  A.  Scope................................................................................................................................................2 
77  B.  Electronic Submissions....................................................................................................................2 
78  C.  Document Information for Previous Submissions...........................................................................2 
79  II.  ELECTRONIC SUBMISSIONS USING THE FDA GATEWAY (ESG)...................2 
80  A.  General Issues..................................................................................................................................2 
81  B.  FDA ESG Preparation, Registration and Policy..............................................................................3 
82  III.  ELECTRONIC SUBMISSIONS USING PHYSICAL MEDIA (E.G. CD-ROMS)....3 
83  IV.  OTHER INFORMATION ABOUT ELECTRONIC SUBMISSIONS........................4 
84  A.  Electronic Format............................................................................................................................4 
85  B.  Scanned Documents.........................................................................................................................5 
86  C.  PDF Bookmarks and Hypertext Links.............................................................................................5 
87  D.  Cover Letters....................................................................................................................................5 
88  E.  Table of Contents.............................................................................................................................6 
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Guidance for Industry 
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Providing Regulatory Submissions in Electronic Format 
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Orphan-Drug and Humanitarian Use Device Designation  
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Requests and Related Submissions 
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101   
102  This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
103  does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
104  An alternative approach may be used if such approach satisfies the requirements of the applicable statutes 
105  and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
106  implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
107  number listed on the title page of this guidance. 
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110   
111  I.  INTRODUCTION 
112   
113  This is one in a series of guidance documents intended to assist sponsors making regulatory 
114  submissions to the Office of Orphan Products Development (OPD) in electronic format using the 
115  FDA Electronic Submissions Gateway (ESG) pathway or directly to OPD on physical media 
116  (e.g., CD-ROMs).  This guidance discusses issues related to the electronic submission of 
117  requests for orphan-drug designation, humanitarian use device designation (HUD), and related 
118  submissions.  
119   
120  The goals of this guidance are to enhance the receipt, processing, review, and archiving of 
121  electronic submissions to OPD.   
122   
123  In October 2003, the Food and Drug Administration (FDA) issued the draft guidance for industry 
124  Providing Regulatory Submissions in Electronic Format  General Considerations.  The 
125  General Considerations Guidance discusses issues common to all types of electronic regulatory 
126  submissions, such as acceptable file formats, physical media and submission procedures.1  As set 
127  forth under Part 11, Title 21, Code of Federal Regulations, for records submitted to the FDA, 
128  sponsors may elect to use electronic records in lieu of paper records, in whole or part, provided 
129  the requirements of Part 11 are met and the documents or parts of documents to be submitted 
130  have been identified by the FDA in public docket No. 92S-0251 
131  (http://www.fda.gov/ohrms/dockets/dockets/92s0251/92s0251.htm) as being the type of 
132  submission it is prepared to accept in electronic format.2   
                                                 
1  This October 2003 draft guidance is a revision of the General Considerations Guidance of 1999; the revision was 
issued as a draft guidance for public comment in October 2003, and it is available at 
http://www.fda.gov/cder/guidance/4156dft.pdf. 
 
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 
(http://www.fda.gov/cder/guidance/5667fnl.pdf)  
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133  FDA's guidance documents, including this guidance, do not establish legally enforceable 
134  responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
135  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
136  cited.  The use of the word should in Agency guidances means that something is suggested or 
137  recommended, but not required. 
138   
139  A.  Scope 
140   
141  This guidance applies to orphan-drug and humanitarian use device (HUD) designation requests 
142  to OPD as well as related submissions such as amendments, correspondence, and annual reports.   
143   
144  B.  Electronic Submissions 
145   
146  There are two ways you can provide electronic submissions to OPD.  The first and preferred way 
147  is completely electronic through the FDA Electronic Submissions Gateway.  Alternatively, you 
148  may send the submission directly to OPD on physical media with a signed paper cover letter. 
149   
150  We believe it is most beneficial to begin your electronic submissions with the initial submission 
151  of a request for an orphan drug or HUD designation.  However, if you wish to make electronic 
152  submissions to previously submitted requests, please contact OPD first. You should avoid the 
153  submission of any paper documents when you follow the recommendations in this document 
154  except for the signed cover letter that accompanies submissions of physical media directly to 
155  OPD.  You should submit the electronic information for all files following the specifications 
156  associated with this guidance.   
157   
158  Once you begin to submit a specific request in electronic format based on this guidance, 
159  subsequent submissions to the request should continue to be submitted electronically.   
160   
161  C.  Document Information for Previous Submissions 
162   
163  If you have submitted a request for designation in paper form and decide to submit subsequent 
164  related requests (e.g., amendments, correspondence, annual reports) in electronic format based 
165  on this guidance, we do not expect you to provide electronic files for the previous submissions to 
166  the request.  For example, if you submitted an original request in 2001 and now submit an 
167  amendment to the request electronically, we do not expect you to electronically re-submit the 
168  document information for the files submitted in 2001.  
169   
170  II.  ELECTRONIC SUBMISSIONS USING THE FDA GATEWAY (ESG) 
171   
172  A.  General Issues 
173   
174  The Food and Drug Administration (FDA) Electronic Submissions Gateway is an Agency-wide 
175  solution for accepting electronic regulatory submissions.  The FDA ESG enables the secure 
176  submission of regulatory information for review.  The FDA ESG will enable the FDA to process 
177  regulatory information automatically while it functions as:  
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178    A single point of entry for the receipt and processing of all electronic submissions in a 
179  highly secure environment that complies with secure messaging standards  
180    A mechanism for automating current electronic processes such as the electronic 
181  acknowledgment of submissions  
182  The electronic submission process encompasses the receipt, acknowledgment of receipt (to the 
183  sender), routing, and notification to a receiving Center or Office of the delivery of an electronic 
184  submission. 
185  The FDA ESG is the central transmission point for sending information electronically to the 
186  FDA.  Within that context, the FDA ESG is a conduit, or "highway", along which submissions 
187  travel to reach their final destination.  It does not open or review submissions; it automatically 
188  routes them to the proper FDA Center or Office, in this case, the Office of Orphan Products 
189  Development. 
190   
191  B.  FDA ESG Preparation, Registration and Policy 
192   
193  There are a number of preparatory activities that should be completed before beginning the 
194  registration process.  There are also system hardware and software considerations to ensure 
195  compatibility with and security for users of the FDA ESG.  Access the internet webpage 
196  http://www.fda.gov/esg/  for all the information on FDA electronic submission gateway 
197  preparation, registration, and policies.  Questions regarding the process can be directed to: 
198  esgprep@fda.gov. 
199   
200  Once registration has been completed and a digital certificate has been issued to serve as an 
201  electronic signature for the sponsor, submissions to OPD through the ESG should follow the 
202  format outlined in Part IV. OTHER INFORMATION ABOUT ELECTRONIC SUBMISSIONS.  
203  Questions regarding the format of electronic submissions should be directed to the electronic 
204  submission coordinator for orphan-drug designation requests at desigesub@fda.hhs.gov or for 
205  HUD designation requests at hudesub@fda.hhs.gov . 
206   
207  III.  ELECTRONIC SUBMISSIONS USING PHYSICAL MEDIA (E.G. CD-ROMS) 
208   
209  A second option for the electronic submission of documents to FDA is via physical media sent 
210  directly to OPD. This option is completely separate from the ESG.  
211   
212  Physical media should be submitted 1) as described in the General Considerations Guidance 
213  (http://www.fda.gov/cder/guidance/4156dft.pdf); 2) protected (e.g., in a sleeve, jewel case, 
214  physical media mailer); and 3) be attached securely to a jacket (e.g., notebook, binder).   
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216  The jacket should include a signed paper copy of the cover letter for the submission and the 
217  electronic media for archiving.  Note in the cover letter that the submission is in electronic 
218  format and is virus free with a description of the software (name, version, and company) used to 
219  check the files for viruses. 
220   
221  Each unit of physical media and its jacket should be labeled with the following: 
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222   
223    Orphan-Drug Designation or Humanitarian Use Device Designation Request 
224    Designation Request # (e.g., D061234 for drugs or H061234 for devices, if 
225  known) 
226    Company Name 
227    Drug or Device Name 
228    Submission Type (original, amendment, annual report, or correspondence) 
229    Submission Date 
230    Disk/CD-ROM (total number submitted, i.e., # of #) 
231    Point of Contact for the Electronic Submission (name and telephone number) 
232   
233  A jacket can contain more than one unit of physical medium. If more than one unit of physical 
234  medium is contained in the jacket, the label on the jacket should include the number of units of 
235  physical media in the jacket (e.g., Jacket contains 2 CD-ROMs), and each unit of the physical 
236  media should be numbered in series as appropriate (e.g., 1 of 2, 2 of 2).   
237   
238  You can direct questions to OPD regarding the preparation of physical media electronic 
239  submissions for orphan-drug designation requests at desigesub@fda.hhs.gov or for humanitarian 
240  use device designation requests at hudesub@fda.hhs.gov or 301-827-3666. 
241   
242  These physical media should be sent to OPD at the following address: 
243   
244    Office of Orphan Products Development  
245    Food and Drug Administration  
246    Room 6A-55, HF-35 
247  5600 Fishers Lane 
248  Rockville, Maryland 20857 
249   
250  IV.  OTHER INFORMATION ABOUT ELECTRONIC SUBMISSIONS  
251   
252  A.  Electronic Format 
253   
254  Documents submitted in electronic format should: 
255   
256    Enable the user to easily view a clear and legible copy of the information  
257   
258    Include a well-structured table of contents and allow the user to navigate easily 
259  through the submission  
260   
261    Enable the user to print each document page by page, as it would have been 
262  provided in paper, maintaining fonts, special orientations, table formats, and page 
263  numbers 
264   
265    Allow the user to copy text, images and data electronically into other common 
266  software formats. 
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267  To achieve the above goals, all electronic documents should be submitted in text-based format if 
268  possible.  References such as publications may be submitted in portable document format (PDF).  
269  PDF is an open, published format created by Adobe Systems Incorporated 
270  (http://www.adobe.com).  You do not need to use a product from Adobe or from any specific 
271  company to produce your PDF documents. 
272   
273  B.  Scanned Documents 
274   
275  In general, documents scanned into text-based format are more useful for review than image-
276  based documents.  Image-based documents are more difficult to read, cannot be electronically 
277  searched, take longer to print, and occupy more storage space than text-based documents. 
278  Therefore, when possible, you should provide text-based documents, rather than image files.  We 
279  understand that certain documents, such as handwritten documents and documents generated 
280  independently by your company (such as journal publications) may be available only in paper.  
281  Such paper documents can be scanned and submitted in electronic format as image-based files.  
282  However, we expect documents such as study reports recently generated by the company or 
283  recently generated as the result of the company's request to a third party to be available as text-
284  based documents.   
285   
286  C.  PDF Bookmarks and Hypertext Links 
287   
288  Bookmarks and hypertext links are extremely important for efficient navigation through 
289  documents.  For documents with a table of contents, you should provide bookmarks and 
290  hypertext links for each item listed in the table of contents including tables, figures, publications, 
291  references, and associated appendices.  The bookmark hierarchy should be identical to the table 
292  of contents. Hypertext links should be included throughout the body of the document to support 
293  annotations, related sections, references, appendices, tables, or figures that are not located on the 
294  same page.  It is preferable to provide the hypertext links directly to the appropriate PDF 
295  publication reference file.  The link should open in a separate window and enable the user to 
296  return to the exact location in the body of the document where the link was located when it is 
297  closed. 
298  D.  Cover Letters 
299   
300  A cover letter should be provided with the request. If the request is made through the FDA ESG, 
301  the cover letter will only be submitted electronically (that is, there will be no paper copy), will be 
302  located inside the request, and would be considered archival.  For submissions made directly to 
303  OPD on physical media, a signed paper copy of the electronic version should be submitted with 
304  the accompanying the CD-ROMs.  All cover letters should include the following: 
305   
306    Description of the submission including appropriate regulatory information 
307   
308    Description of the electronic submission including the type and number of electronic 
309  media used (e.g., # of CD-ROMs), and the approximate size of the submission (e.g., 2 
310  gigabytes) 
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312    Statement that the submission is virus free with a description of the software (name, 
313  version, and company) used to check the files for viruses 
314   
315    The regulatory and information technology (IT) points of contact for the application. 
316   
317  E.  Table of Contents 
318   
319  The Table of Contents should contain the required information and be organized as described in 
320  the regulations, Part 316-Orphan Drugs, Subpart C-Designation of an Orphan Drug (21 CFR 
321  316.20 Content and format of a request for orphan-drug designation request)(see Table 1), 
322  Annual Reports (Part 316.30  Annual reports of holder of orphan-drug designation), or Part 814-
323  Premarket Approval of Medical Devices, Subpart H-Humanitarian Use Devices (21 CFR 
324  814.102 Request for designation)(see Table 2).   
325   
326  Table 1:  Items in an Orphan-Drug Designation Request as described in 21 CFR 316.20 
Item  Description 
    Table of contents (Index) 
1  Statement of orphan-drug designation request                                      (316.20(b)(1)) 
2  Information on sponsors contact person or resident agent                   (316.20(b)(2)) 
3  Description of rare disease or condition                                                (316.20(b)(3)) 
4  Description of the drug and rationale for use                                        (316.20(b)(4)) 
5  Clinical superiority explanation, if applicable                                       (316.20(b)(5)) 
6  Drug for use in an orphan subset, if applicable                                  (316.20(b)(6)) 
7  Summary of regulatory status and marketing history of the drug         (316.20(b)(7)) 
8  Prevalence of drugs target population or cost recovery, if applicable (316.20(b)(8)) 
9  Statement of real party of interest                                                          (316.20(b)(9)) 
10  Other, if applicable 
327   
328  Table 2:  Items in a HUD Designation Request as described in 21 CFR 814.102 
Item  Description 
  Table of contents (Index) 
1  Statement of humanitarian use device designation request                  (814.102(a)(1)) 
2  Information on sponsors contact person or resident agent                  (814.102(a)(2)) 
3  Description of the targeted disease or condition                                  (814.102(a)(3)) 
4  Description of the device and rationale for use                                    (814.102(a)(4)) 
5  Demonstration of the devices target population                                  (814.102(a)(5))  
6  Other (e.g., regulatory summary) 
329   
330  The table of contents, hypertext links, and bookmarks in the electronic version of a submission 
331  play the same role as the index by volume, section, and page number utilized in a paper copy.  
332  The table of contents may contain multiple levels of detail, that is, tables of subcontents. The 
333  first level of detail simply lists the items in the designation request.  The second level of detail 
334  provides additional information regarding the contents for each item.  Bookmarks and hyperlinks 
335  for each document or dataset should be listed for and linked to the appropriate file. 
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336  The following is an example of a portion of a Table of Contents for an orphan-drug designation 
337  request using some of the headings describing required information under 21 CFR 316.20.  A 
338  Table of Contents for a HUD designation request would be similar and include headings 
339  describing required information under 21 CFR 814.102. 
340   
341  1.  STATEMENT OF THE ORPHAN-DRUG DESIGNATION REQUEST 
342  2.  GENERAL INFORMATION 
343    3.1  Sponsor contact information 
344    3.2  Primary contact  
345    3.3  Manufacturer of the drug 
346  3.  DESCRIPTION OF THE RARE DISEASE OR CONDITION / PROPOSED INDICATION 
347    3.1  Details of the condition 
348      3.1.1.  Diagnosis and screening   
349      3.1.2.  Treatment 
350      3.1.3.  Reasons why treatment is needed 
351  3.2  Proposed indication 
352  4.  DESCRIPTION OF THE DRUG / SCIENTIFIC RATIONALE FOR USE 
353    4.1  Description of the drug 
354    4.2  Mode of Action 
355    4.3  Rationale for use in proposed indication 
356  5.  REGULATORY SUMMARY 
357  6.  PREVALENCE OF TARGET POPULATION 
358   
359  F.  Submission of amendments, annual reports, and correspondence 
360   
361  The electronic submissions of amendments, annual reports, and correspondence relating to 
362  documents previously submitted to OPD should be submitted under the original designation 
363  reference number (e.g., D061234 for an orphan-drug designation request; e.g., H061234 for a 
364  HUD designation request).   
365   
366  If appropriate, cover letters and tables of contents should be submitted and above guidelines 
367  should be followed with regard to format, scanning, bookmarks, and hypertext links.  
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