IND Submissions for 
Individualized Antisense 
Oligonucleotide Drug 
Products: Administrative and 
Procedural Recommendations 
Guidance for Sponsor-Investigators 
 
 
 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 electronic comments to http://www.regulations.gov.  Submit written 
comments to the Dockets Management (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 (CDER) Colleen Locicero at 301-796-1114. 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2021 
Procedural 
 
35165469dft.docx 
12/29/20   
IND Submissions for 
Individualized Antisense 
Oligonucleotide Drug 
Products: Administrative and 
Procedural Recommendations 
Guidance for Sponsor-Investigators 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2021 
Procedural 
   
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  AGENCY INTERACTIONS ........................................................................................... 2 
A.  Importance of Early FDA Interaction ......................................................................................... 2 
B.  Established Communication Plan ................................................................................................ 3 
C.  Confidentiality Concerns for Outside Participants .................................................................... 3 
D.  Secure Email and Faxes ................................................................................................................. 4 
IV.  SUBMISSION EXPECTATIONS ................................................................................... 4 
A.  General ............................................................................................................................................ 4 
B.  Pre-IND Meeting Package ............................................................................................................. 5 
1. Content ............................................................................................................................................. 5 
2. Format ............................................................................................................................................. 5 
C.  Application ..................................................................................................................................... 6 
1. Nonclinical Report Format .............................................................................................................. 6 
2. Chemistry, Manufacturing, and Controls Report Format ............................................................... 6 
3. Safety and Annual Reports ............................................................................................................... 7 
a.  Safety reports ............................................................................................................................ 7 
b.  Annual reports ........................................................................................................................... 7 
D.  Ethical and Human Subject Protection Considerations ............................................................. 8 
1. IRB Review ....................................................................................................................................... 8 
2. Informed Consent ............................................................................................................................. 8 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  IND Submissions for Individualized Antisense Oligonucleotide Drug 
2  Products: Administrative and Procedural Recommendations 
3  Guidance for Sponsor-Investigators1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  This guidance is intended for sponsor-investigators2 (hereafter referred to as sponsors) 
18  developing individualized investigational antisense oligonucleotide (ASO) drug products for a 
19  severely debilitating or life-threatening genetic disease.3  Most often, individuals with such 
20  diseases will not have FDA-approved treatment options and their diseases will be rapidly 
21  progressing, resulting in early death and/or devastating irreversible morbidity within a short time 
22  frame.  In these situations, drug development targeted at a larger number of patients with the 
23  ASO is not anticipated because of the specificity of the mechanism of action of the ASO drug 
24  product combined with the rarity of the treatment-amenable patient population. 
25   
26  The focus of this guidance is on administrative and procedural aspects of interacting with FDA 
27  on development programs for individualized ASO drug products, such as the approach to 
28  obtaining feedback from FDA and the expectations and process for making regulatory 
29  submissions to FDA.  The guidance provides high-level recommendations about informed 
30  consent and the requirement for institutional review board (IRB) review of protocols for trials of 
31  individualized ASO drug products.  This guidance also addresses the initial development of these 
32  individualized ASO drug products; it does not address regulatory considerations for the 
33  development of these drug products for marketing and continued, long-term treatment of patients 
34  with the disease for which the drug product is being developed.  This guidance also does not 
35  address the nonclinical data, the clinical data, or the product quality requirements that must be 
36  met to initiate administration of these individualized ASO drug products in humans. 
                                                 
1 This guidance has been prepared by the Office of New Drug Policy in the Center for Drug Evaluation and 
Research at the Food and Drug Administration. 
 
2 A sponsor-investigator is an individual who both initiates and conducts an investigation, and under whose 
immediate direction the investigational drug is administered or dispensed.  The term does not include any person 
other than an individual (see 21 CFR 312.3(b)). 
 
3 Severely debilitating means diseases or conditions that cause major irreversible morbidity.  Life-threatening means 
diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and those 
with potentially fatal outcomes, where the endpoint of clinical trial analysis is survival (see 21 CFR 312.81). 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
37   
38  Although the guidance is intended to help sponsors seeking to develop an individualized ASO 
39  drug product, the principles and practices outlined in the guidance may also be applicable to 
40  developing other types of individualized drug products (i.e., non-ASO).  Sponsors who consider 
41  applying the principles outlined in this guidance for non-ASO individualized drug products 
42  should first consult with the appropriate review division. 
43   
44  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
45  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
46  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
47  the word should in Agency guidances means that something is suggested or recommended, but 
48  not required. 
49   
50   
51  II.  BACKGROUND 
52   
53  Typically, a drug research and development program begins with identifying a moiety intended 
54  to treat a disease or condition and subsequently evaluating that drug in animal4 and then human 
55  studies.  Clinical development programs vary considerably in size and complexity, depending on 
56  disease prevalence, the heterogeneity of the condition, disease course, and many other factors.  
57  Once a drug product is approved for marketing, patients other than those who participated in 
58  clinical trials will have access to, and are expected to benefit from, treatment with that drug 
59  product for its approved use or uses. 
60   
61  Advances in scientific knowledge and drug development technology, however, provide an 
62  opportunity for new approaches in drug development.  Contemporary approaches to genetic 
63  testing and molecular diagnosis can elucidate, in certain circumstances, the precise etiology of a 
64  specific patients genetic disease.  For a patient with an extremely rare disease-causing genetic 
65  variant, development of an individualized ASO drug product that is tailored to the patients 
66  specific genetic variant may be possible. 
67   
68   
69  III.  AGENCY INTERACTIONS 
70   
71  A.  Importance of Early FDA Interaction 
72   
73  Those participating in these development programs will have a severely debilitating or life-
74  threatening genetic disease for which there is no adequate available therapy and will generally 
75  require prompt medical intervention because of rapid disease progression.  Therefore, 
76  investigators will wish to initiate administration of the investigational drug product rapidly. 
77   
                                                 
4 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible.  We 
encourage sponsors to consult with us if it they wish to use a nonanimal testing method they believe is suitable, 
adequate, validated, and feasible.  We will consider if such an alternative method could be assessed for equivalency 
to an animal test method.   
 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
78  FDA recommends that sponsors request a pre-investigational new drug application (pre-IND) 
79  meeting with the appropriate review division as soon as a participant and at least one potential 
80  individualized ASO drug product (for which there are convincing proof-of-concept data) are 
81  identified.  Early FDA interaction will help sponsors to prepare an adequate IND submission for 
82  review by the Agency and facilitate prompt administration of the investigational drug product.5 
83   
84  B.  Established Communication Plan 
85   
86  As discussed in more detail in the guidance for industry and review staff Best Practices for 
87  Communication Between IND Sponsors and FDA During Drug Development (December 2017),6 
88  FDA recommends establishing a communication strategy with FDA. 
89   
90  A communication strategy can establish the preferred method (e.g., email, telephone) and 
91  frequency of communications.  The strategy may also set expectations related to the timing of 
92  responses to inquiries and requests for information for both the sponsor and FDA.  FDA staff 
93  will strive to respond to sponsor questions and requests promptly and comprehensively. 
94   
95  FDA staff will not communicate about a sponsors development program or IND or the progress 
96  of FDAs review of the program or IND with individuals other than the sponsor (e.g., trial 
97  participant, family member, or other advocate) unless the individual has been designated by the 
98  sponsor as an authorized representative of the sponsor. 
99   
100  C.  Confidentiality Concerns for Outside Participants 
101   
102  If a trial participant, family member, or other advocate attends a meeting between a sponsor and 
103  FDA to discuss the sponsors application, whatever the sponsor or FDA shares at a meeting 
104  about the application may be considered a public disclosure of the sponsors confidential 
105  information (confidential commercial information and/or trade secret information (21 CFR 
106  20.61)) unless, prior to the meeting, the sponsor and the outside participant(s) have entered into a 
107  confidentiality agreement with each other.  In the absence of such a confidentiality agreement, 
108  under FDAs regulations on uniform access (21 CFR 20.21), any confidential information about 
109  an application that is disclosed to an outside participant in this way generally is available to all 
110  members of the public, including under the Freedom of Information Act. 
111   
112  If a sponsor informs FDA that an outside participant will be attending a scheduled meeting 
113  between the sponsor and FDA, the Agency will ask the sponsor 1) to certify in writing, prior to 
114  the meeting, that the sponsor understands that if an outside participant (e.g., trial participant, 
115  family member, or other advocate) attends a meeting with the Agency to discuss the sponsors 
116  application, whatever information is discussed by the sponsor or FDA at the meeting about the 
                                                 
5 Information on pre-IND meetings, including how to request such a meeting, can be found in the draft guidance for 
industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products (December 2017).  
When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents. 
 
6 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
117  sponsors application may be considered a public disclosure of the sponsors confidential 
118  commercial and/or trade secret information unless, prior to the meeting, the sponsor and the 
119  outside participant(s) have entered into a confidentiality agreement with each other, and 2) if 
120  such a confidentiality agreement is in place, to certify in writing as such.  If the sponsor certifies 
121  that such a confidentiality agreement is in place between it and an outside participant, FDA 
122  generally would not consider the presence of that outside participant at a scheduled meeting 
123  between the sponsor and FDA to trigger uniform access with respect to information discussed at 
124  that meeting.  FDA encourages sponsors to resolve these issues promptly to avoid unnecessarily 
125  delaying the meeting. 
126   
127  D.  Secure Email and Faxes 
128   
129  Outside of regulatory submissions to a sponsors application, communication between a sponsor 
130  and FDA will often be conducted via email.  Communication via unsecured email should not 
131  include confidential commercial information, trade secret information, or trial participant 
132  information (21 CFR 20.21; 21 CFR 20.63).  Accordingly, FDA recommends that sponsors 
133  establish a secure email with FDA to allow for communications that may include such 
134  information.  Sponsors can contact the Office of Information Management and Technology to 
135  request secure email.7 
136   
137  Faxes may be used for communication between sponsors and FDA when secure email has not 
138  been established.  Before transmitting faxes, sponsors and FDA regulatory project managers 
139  should contact their counterparts to arrange for confirmation of receipt of the fax. 
140   
141  Communications via fax or secure email do not substitute for formal regulatory submissions, 
142  which are required, for example, for submitting original IND applications and amendments to an 
143  IND (21 CFR 312.23, 312.30, 312.31). 
144   
145   
146  IV.  SUBMISSION EXPECTATIONS 
147   
148  A.  General 
149   
150  Complete and well-organized submissions, in a format conducive to scientific review, can help 
151  increase the efficiency of FDAs review and prevent delays in FDA responses to requests for 
152  information.  All IND submissions should include overall summaries with enough detail to allow 
153  FDA staff to understand the regulatory and developmental context of the submission. 
154   
155  Although it is not required that research INDs8 for developing individualized ASO drug 
156  products, and other related documents, be submitted in electronic format, FDA recommends 
                                                 
7 Direct inquiries to secureemail@fda.hhs.gov. 
 
8 A research IND is an IND for which the sponsor does not intend to commercialize the product.  See the 
information in the section on Field 6B:  IND TYPE in the Instructions for Filling Out Form FDA 1571. 
 
 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
157  electronic submission to facilitate and expedite review of the submissions.  Electronic 
158  submissions for research INDs are not required to be in electronic Common Technical Document 
159  (eCTD) format; however, they may be voluntarily submitted in that format.9 
160   
161  Under FDAs IND regulations at 21 CFR 312.23(b), a sponsor ordinarily is not required to 
162  resubmit information previously submitted to FDA but instead may incorporate the information 
163  by reference.  If the information is in an existing IND application, the sponsor should identify the 
164  IND number, type of submission in which the information is located (e.g., nonclinical 
165  information amendment), the date of submission, page number(s), and, if applicable, volume 
166  number.  If a sponsor seeks to reference information submitted to the Agency by a person other 
167  than the sponsor, the sponsor should include a written statement authorizing such reference that 
168  is signed by the person who submitted the information.  However, in either instance, depending 
169  on when the information was submitted and its format (e.g., paper versus electronic), voluntarily 
170  resubmitting the information may facilitate and expedite FDAs review. 
171   
172  Formal submissions in paper or non-eCTD electronic format should be mailed to the CDER 
173  Central Document Room located at 5901-B Ammendale Road in Beltsville, Maryland.  Sponsors 
174  submitting in paper format are expected to send their applications in triplicate, with one original 
175  and two copies of the submission. 
176   
177  B.  Pre-IND Meeting Package 
178   
179  1.  Content 
180   
181  The package should include information to justify the proposal to develop an individualized 
182  ASO drug product.  Generally, the content of a pre-IND meeting package should also include 
183  information to support proof of concept, initial dosing in humans, and safety monitoring plans 
184  for initial human dosing, as well as the proposed clinical protocol.  Furthermore, the package 
185  should include the nonclinical, bioinformatic (information related to the design of the 
186  oligonucleotide), and product quality data that the sponsor intends to submit with its IND. 
187   
188  2.  Format 
189   
190  The content of a meeting package, including for pre-IND meetings, should be organized 
191  according to the proposed meeting agenda.10  The package should be a sequentially paginated 
192  document with a table of contents, appropriate indices, appendices, and cross references. 
193   
194  The questions for discussion with FDA should be grouped by FDA review discipline and 
195  prefaced with a summary that provides context and explains the need for the question.  The 
                                                 
9 General information on the electronic submission of regulatory information to FDA can be found at 
https://www.fda.gov/drugs/forms-submission-requirements/electronic-regulatory-submission-and-review, and 
information on formal submissions made electronically in eCTD format can be found at 
https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-technical-document-
ectd. 
 
10 For more information, see the draft guidance for industry Formal Meetings Between the FDA and Sponsors or 
Applicants of PDUFA Products.  When final, this guidance will represent the FDAs current thinking on this topic. 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
196  summaries should describe the results of relevant studies.  Any conclusions that result from these 
197  studies, and how they influenced the proposed treatment plan, should be stated clearly. 
198   
199  C.  Application 
200   
201  When the sponsor has gathered the recommended information, the sponsor should submit a 
202  research IND to FDA.  To aid FDA in understanding the proposed development context and 
203  related benefit-risk considerations, the sponsor should include in the initial IND submission the 
204  justification for developing an individualized ASO drug product.  During the pre-IND meeting, 
205  or at some other point before submitting the IND, the sponsor should discuss expectations for the 
206  content of the IND submission with the relevant FDA review division, since some of the content 
207  and format requirements at 21 CFR 312.23 may not be relevant for this type of application. 
208   
209  1.  Nonclinical Report Format 
210   
211  Because the proposed study will be first in humans, it is unlikely that human data will be 
212  available at the time of the initial IND submission. Thus, only product manufacturing and quality 
213  information, bioinformatic (information related to the design of the oligonucleotide), and 
214  nonclinical data will support the safety of initiating administration to a participant.  It is critical 
215  that the nonclinical data be adequately presented and documented. 
216   
217  Sponsors should provide a complete report for each in vitro and in vivo study intended to 
218  characterize the pharmacological activity and the safety of the investigational drug.  Each study 
219  report should include, but not be limited to, the following: 
220   
221    A statement of the purpose of the study 
222   
223    A detailed description of the control and test article (e.g., purity, stability), study design 
224  (e.g., control, dose levels, number of animals per sex per group), animal species or 
225  model, methodology used, and parameters assessed 
226   
227    Complete data sets for all parameters evaluated (e.g., individual animal line listings and 
228  summary data tables) 
229   
230    Analysis and interpretation of the results 
231   
232    Conclusions 
233   
234  General content and format recommendations for the submission of nonclinical data and 
235  information can be found in the guidance for industry Guideline for the Format and Content of 
236  the Nonclinical Pharmacology/Toxicology Section of an Application (February 1987). 
237   
238  2.  Chemistry, Manufacturing, and Controls Report Format 
239   
240  The guidance for industry Content and Format of Investigational New Drug Applications (INDs) 
241  for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
242  Products (November 1995) provides information on general formatting expectations, including 
243  for the chemistry, manufacturing, and control information section of the IND submission.  FDA 
244  recommends that as much information as possible be provided on the drug substance and drug 
245  product, as follows: 
246   
247  Drug Substance 
248   
249    Summary report containing a brief description of the drug substance 
250    Name and address of the manufacturer 
251    General method of preparation, including a flow diagram of the manufacture process 
252    Specifications 
253    Stability information 
254   
255  Drug Product 
256   
257    A list of all components, and their quality, used in the manufacture of the drug product 
258    Quantitative composition 
259    Name and address of the manufacturer 
260    Brief, general description of manufacturing method and packaging procedures, including 
261  a flowchart 
262    Copy of the certificate of analysis for the clinical lot 
263    Specifications 
264    Stability information 
265    A copy of investigational labels and labeling per 21 CFR 312.23(a)(7)(iv)(d) 
266    Claim for categorical exclusion per 21 CFR 312.23(a)(7)(iv)(e) 
267   
268  3.  Safety and Annual Reports 
269   
270  a.  Safety reports 
271   
272  The sponsor of an IND must notify FDA in an IND safety report of potential serious risks as 
273  soon as possible, but in no case later than 15 calendar days, after the sponsor determines the 
274  information qualifies for reporting (21 CFR 312.32(c)(1)). 
275   
276  The sponsor should submit each report in a narrative format or on Form FDA 3500A or in 
277  electronic format.11 
278   
279  b.  Annual reports 
280   
281  The sponsor of an IND shall, within 60 days of the anniversary date that the IND went into 
282  effect, submit a brief report of the progress of the investigation (21 CFR 312.33). 
283   
                                                 
11 For more information, see the draft guidance for industry Providing Regulatory Submissions in Electronic 
Format:  IND Safety Reports (October 2019).  When final, this guidance will represent the FDAs current thinking 
on this topic. 
7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
284  D.  Ethical and Human Subject Protection Considerations 
285   
286  Because of the nontraditional nature of drug development in this arena, complex ethical issues 
287  may arise.  As such, sponsors should consider conferring with a medical ethicist when 
288  developing their protocol. 
289   
290  1.  IRB Review 
291   
292  Under FDA regulations, a protocol under which an individualized ASO drug product is 
293  administered to a human subject must be reviewed by an IRB (21 CFR Part 56), which must 
294  fully evaluate the protocol and ensure that risks to the subject are reasonable in relation to the 
295  anticipated benefits (21 CFR 56.111(a)(2)).  The IRB should be provided with the results of all 
296  relevant nonclinical safety studies in animals that have been conducted.  Sponsors should 
297  consider contacting their IRB as early as possible.  If the ASO drug product will be administered 
298  to a child, the IRB must ensure that the protocol complies with the requirements under 21 CFR 
299  part 50, subpart D. 
300   
301  2.  Informed Consent 
302   
303  Under FDA regulations, informed consent must be obtained under circumstances that provide 
304  prospective participants, or their legally authorized representatives, sufficient opportunity to 
305  consider whether to participate and that minimize the possibility of coercion or undue influence 
306  (21 CFR 50.20).  The sponsor should include a copy of the informed consent document in the 
307  original IND submission. 
308   
309  The informed consent document and the consent discussion should appropriately emphasize in a 
310  clear manner that the ASO drug product is experimental, the reality that the benefit is uncertain 
311  and the potential risks are unknown, and that additional costs to the participant may be associated 
312  with the administration of the drug product.  When appropriate, the consent document and 
313  consent discussion should include information that the administration of the ASO drug product 
314  will be the first use in humans of the investigational drug and relevant information from 
315  nonclinical safety studies in animals that have been conducted that could potentially inform the 
316  safety of the participant. 
8