IND Submissions for 
Individualized Antisense 
Oligonucleotide Drug Products 
for Severely Debilitating or 
Life-Threatening Diseases: 
Clinical 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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (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) Eithu Lwin at 301-796-0728.  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2021 
Clinical/Medical 
44890102dft.docx 
12/3/2021   
IND Submissions for 
Individualized Antisense 
Oligonucleotide Drug Products 
for Severely Debilitating or 
Life-Threatening Diseases:  
Clinical 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) 
 
December 2021 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  CLINICAL CONSIDERATIONS ................................................................................... 3 
A.  Ethical and Human Subject Protection Considerations ............................................................. 3 
B.  Diagnostic and Genetic Considerations ....................................................................................... 3 
C.  Dosing Considerations ................................................................................................................... 4 
D.  Drug Product Administration Procedures .................................................................................. 5 
E.  Safety Assessment .......................................................................................................................... 5 
F.  Assessment of Clinical Response .................................................................................................. 6 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  IND Submissions for Individualized Antisense Oligonucleotide Drug 
2  Products for Severely Debilitating or Life-Threatening Diseases:  
3  Clinical Recommendations   
4  Guidance for Sponsor-Investigators1 
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  This guidance is intended for sponsor-investigators2 (hereafter referred to as sponsors) 
19  developing individualized investigational antisense oligonucleotide (ASO) drug products for a 
20  severely debilitating or life-threatening (SDLT) genetic disease.3 Most often, individuals with 
21  such diseases will have no alternative treatment options, and their diseases will be rapidly 
22  progressing, resulting in early death and/or devastating or irreversible morbidity within a short 
23  time frame without treatment. In these situations, drug development targeted to a larger number 
24  of patients with the same disease is not anticipated because of the specificity of the mechanism 
25  of action of the ASO combined with the rarity of the treatment-amenable patient population. The 
26  gene variant or variants that are targeted by the ASO drug product should be unique to the trial 
27  participant(s) and generally only reported in a small number of patients (typically 1 to 2) in the 
28  disease population. If more than a few patients may be candidates for targeted treatment with the 
29  ASO drug product, then the ASO is no longer considered individualized, and the sponsor should 
30  discuss a drug development plan of the investigational ASO drug product for a larger patient 
31  population with the relevant review division. 
32   
33  The focus of this guidance is to describe important clinical considerations for investigational new 
34  drug application (IND) submissions to support initial and continued administration, dosing, and 
35  clinical monitoring of an individual with a SDLT disease attributable to a unique genetic 
 
1 This guidance has been prepared by the Office of New Drugs and the Office of Translational Sciences, Office of 
Clinical Pharmacology, 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 
36  variant(s) that may be amenable to an ASO drug product. The individualized ASO drug product 
37  should belong to a well-characterized chemical class4 (i.e., a chemical class for which there is 
38  substantial nonclinical information and clinical experience that is either publicly available or to 
39  which the sponsor has right of reference).   
40   
41  This guidance does not address clinical and regulatory considerations for the development of an 
42  individualized ASO drug product for commercial marketing. This guidance also does not address 
43  the nonclinical data5 or the drug product quality requirements6 to initiate administration of an 
44  individualized ASO drug product in humans, or the administrative and procedural 
45  recommendations for an IND submission.7  
46   
47  The contents of this document do not have the force and effect of law and are not meant to bind 
48  the public in any way, unless specifically incorporated into a contract. This document is intended 
49  only to provide clarity to the public regarding existing requirements under the law. FDA 
50  guidance documents, including this guidance, should be viewed only as recommendations, unless 
51  specific regulatory or statutory requirements are cited. The use of the word should in FDA 
52  guidances means that something is suggested or recommended, but not required. 
53   
54   
55  II.  BACKGROUND 
56   
57  Advances in technology may now allow targeting of a drug product to the molecular changes 
58  that underlie an individuals genetic disease (e.g., gene deletions, rearrangements). This field is 
59  rapidly evolving, and the clinical considerations for evaluating the safety and efficacy of these 
60  drug products may differ from the considerations for larger development programs. This 
61  guidance provides recommendations for managing the administration of the individualized ASO 
62  drug product and conducting clinical assessments of the safety and treatment response during 
63  administration of the ASO drug product. The recommendations in this guidance are informed by 
64  experience with certain classes of well-characterized ASO drug products and by the ability to 
65  anticipate and manage some of the potential adverse events based on this prior experience with 
 
4 Examples of well-characterized, antisense chemical classes, based on prior FDA experience, include single-
stranded phosphorothioate or mixed phosphorothioate/phosphodiester, 2-methoxyethyl substituted oligonucleotides 
(by systemic or intrathecal route), and phosphorodiamidate morpholino oligonucleotides (by systemic route). 
 
5 See the draft guidance for sponsor-investigators Nonclinical Testing of Individualized Antisense Oligonucleotide 
Drug Products for Severely Debilitating or Life-Threatening Diseases (April 2021). 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 See the draft guidance for sponsor-investigators IND Submissions for Individualized Antisense Oligonucleotide 
Drug Products for Severely Debilitating or Life-Threatening Diseases: Chemistry, Manufacturing, and Controls 
Recommendations (December 2021). When final, this guidance will represent the FDAs current thinking on this 
topic. 
 
7 See the draft guidance for sponsor-investigators IND Submissions for Individualized Antisense Oligonucleotide 
Drug Products: Administrative and Procedural Recommendations (January 2021). When final, this guidance will 
represent the FDAs current thinking on this topic. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
66  the ASO drug classes. The following sections outline important clinical considerations and, when 
67  applicable, information to include in IND submissions. 
68   
69   
70  III.  CLINICAL CONSIDERATIONS 
71   
72  A.  Ethical and Human Subject8 Protection Considerations 
73   
74  Under FDA regulations, a protocol under which an individual ASO drug product is administered 
75  to a human subject must be reviewed and approved by an institutional review board (IRB) before 
76  it is allowed to proceed (21 CFR part 56). If children9 are to be included in the protocol, the 
77  requirements in 21 CFR part 50, subpart D (Additional Safeguards for Children in Clinical 
78  Investigations) also must be met. Similarly, in accordance with 21 CFR 50.20, the sponsor must 
79  obtain legally effective informed consent from the trial participant, or the participants legally 
80  authorized representative, before administration of the investigational ASO drug product. The 
81  informed consent must include all the required basic elements under 21 CFR 50.25(a), including, 
82  but not limited to, a description of reasonably foreseeable risks or discomforts to the trial 
83  participant and any potential benefits which may reasonably be expected from the investigational 
84  ASO drug product. When appropriate, significant new findings developed during the course of 
85  the research that might have implications for the trial participants willingness to continue in the 
86  research should be provided to the participant (and/or the participants legally authorized 
87  representative). In addition, the sponsor should discuss with the applicable IRB how and when 
88  significant new findings will be provided to the trial participant.10   
89   
90  B.  Diagnostic and Genetic Considerations 
91   
92  Sponsors should consider the following recommendations for characterizing the targeted gene 
93  variant(s) and the trial participants clinical diagnosis and include all relevant information in the 
94  IND submission: 
95   
96    The trial participants clinical and genetic diagnosis should be confirmed through 
97  relevant laboratory testing (e.g., gene sequencing, enzymatic analysis, biochemical 
98  testing, imaging evaluations, as applicable). Sponsors should appropriately validate 
99  laboratory assays for their intended use. Sponsors should provide all results in the IND 
100  submission. 
101   
102    Sponsors should provide evidence that establishes the role of the gene variant(s) targeted 
103  by the ASO drug product in the pathogenesis of the trial participants disease. If the 
 
8 For the purposes of this guidance, FDA uses the terms subject and participant interchangeably.  
 
9 21 CFR 50.3(o) defines children as persons who have not attained the legal age for consent to treatments or 
procedures involved in clinical investigations, under the applicable law of the jurisdiction in which the clinical 
investigation will be conducted. 
 
10 For additional information about FDAs recommendations on informed consent, see the draft guidance for IRBs, 
clinical investigators, and sponsors Informed Consent Information Sheet (July 2014). When final, this guidance will 
represent the FDAs current thinking on this topic.   
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
104  evidence is insufficient, additional investigation(s) may be needed before initiating use of 
105  the ASO drug product. 
106   
107    Sponsors should provide evidence that the identified gene variant or variants are unique 
108  to the trial participant, including (a) prevalence estimates of the targeted gene variant(s) 
109  in the disease and (b) the projected incidence of the targeted variant(s) in new cases of the 
110  disease based on molecular genetic considerations (e.g., type of mutation (missense, 
111  frameshift, other), location in the protein).  
112   
113  C.  Dosing Considerations 
114   
115  Sponsors should consider the following recommendations for dosing of investigational ASO 
116  drug products and include all relevant information in the IND submission: 
117   
118    The starting dose should be based on available nonclinical data and be scientifically 
119  supported by available information from other ASO drug products in the chemical class 
120  and/or prior clinical experience. In general, the starting dose should be expected to have a 
121  pharmacologic effect, based on available nonclinical in vitro and/or in vivo data.11  
122   
123    The sponsor should calculate the starting dose based on interspecies dose comparisons.5  
124   
125    Given the limited nonclinical data that may be available when dosing is initiated, the 
126  sponsor should consider a dose escalation approach where dosing is initiated and 
127  escalated to higher doses based on pharmacodynamic (PD) effects and/or trial participant 
128  response to the investigational ASO drug product (tolerability or perceived benefit) and 
129  available nonclinical data. The protocol should contain a clear dosing plan and 
130  justification for selecting the starting dose, dosing interval, and plan for dose escalation 
131  or dose reduction for toxicity. If a loading dose or doses are proposed, the protocol 
132  should contain a rationale for using a loading dose(s) and maintenance dose interval(s) 
133  based on considerations such as the ASO drug products half-life, likely distribution (e.g., 
134  target areas in the central nervous system (CNS), kidney), and anticipated toxicities with 
135  different doses. 
136   
137    Sponsors should increase doses cautiously during dose escalation (e.g., by no more than a 
138  two-fold increment), allowing sufficient time to observe a response to a dose change 
139  before making further modifications. If a steep dose- or exposure-response is observed 
140  for severe toxicities in nonclinical toxicology studies or when no predictive marker of 
141  severe toxicity is available in humans, the sponsor should escalate the dose at smaller 
142  increments (e.g., fractional increments rather than dose doubling). In general, sponsors 
143  should not make concurrent changes to the dose and dosing interval without justification.  
144   
 
11 For additional considerations pertaining to selection of the starting dose, see the draft guidance for sponsor-
investigators Nonclinical Testing of Individualized Antisense Oligonucleotide Drug Products for Severely 
Debilitating or Life-Threatening Diseases. When final, this guidance will represent the FDAs current thinking on 
this topic. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
145    The protocol should specify a plan for de-escalation/discontinuation if a dose-limiting 
146  toxicity develops, and the sponsor should inform the trial participant or the participants 
147  legally authorized representative of the reason(s) for the dose changes. 
148   
149  D.  Drug Product Administration Procedures 
150   
151  Sponsors should consider the following recommendations for administration procedures of 
152  investigational ASO drug products:  
153   
154    Sponsors should administer the starting dose and each escalation in dose in an inpatient 
155  (hospital) setting. For at least 24 hours after administration, the sponsor should monitor 
156  the participant closely for acute, serious adverse events precipitated by the administration 
157  procedure (e.g., intrathecal) or by the ASO drug product itself (e.g., hemodynamic 
158  instability, severe hypersensitivity reactions/anaphylaxis, CNS adverse effects). After the 
159  sponsor adequately characterizes the safety and tolerability at a given dose and any 
160  adverse events are identified and appropriately monitored, it generally would be 
161  acceptable to administer subsequent doses using the same dose in an outpatient (clinic) 
162  setting, if needed, with appropriate safety monitoring and interventions available for 
163  possible serious adverse events (e.g., anaphylaxis).  
164   
165    For intrathecal ASO drug products, experienced medical personnel should perform the 
166  intrathecal administration and administer sedation and/or analgesics if needed for the 
167  procedure. Appropriate medical monitoring and procedural and therapeutic interventions 
168  should be available in case of complications from the procedure and/or the sedation. 
169   
170  E.  Safety Assessment 
171   
172  Sponsors should consider the following recommendations for safety assessments of 
173  investigational ASO drug products and detail all safety procedures and assessments in the IND 
174  submission: 
175   
176    Sponsors should perform routine safety assessments (e.g., adverse events, vital signs, 
177  electrocardiogram, laboratory assessments) while the investigational ASO drug product is 
178  being administered and for a period after stopping administration based on the anticipated 
179  half-life of the ASO drug product. Safety monitoring should be informed by nonclinical 
180  toxicology findings, potential off-target gene knockdown effects predicted by 
181  bioinformatic tools, and previously identified safety risks associated with the use of other 
182  ASO drug products of the same chemical class. The protocol should include a detailed 
183  schedule of safety assessments.  
184   
185    Sponsors should conduct the safety assessments more frequently during the initial dosing 
186  period (e.g., in the first 2 to 3 months). At a minimum, sponsors should conduct and 
187  review safety assessments before each dose, or more frequently if the interval between 
188  doses is long. Based on the initial results, the frequency of safety assessments can then be 
189  decreased. The protocol should clearly outline those assessments. Changes to the 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
190  frequency of assessments should be guided by participants safety and tolerability of the 
191  ASO drug product and emerging data from nonclinical toxicology studies.  
192   
193    Given the potential serious risk of thrombocytopenia observed with phosphorothioate or 
194  mixed-phosphorothioate backbone ASOs, if an ASO drug product of this class is 
195  administered, the sponsor should perform and review platelet count at least every 2 weeks 
196  or before each dose administration, whichever is more frequent. The sponsor should 
197  monitor closely for abnormal findings and associated adverse events (e.g., bleeding, 
198  bruising) to inform decisions about continued ASO drug product administration.  
199   
200    For intrathecally administered ASO drug products, the sponsor should collect 
201  cerebrospinal fluid before each dose administration to evaluate for potential signs of 
202  inflammation and infection. The sponsor should, when feasible and appropriate, use any 
203  remaining sample(s) for pharmacokinetic (PK) assessments or relevant biochemical 
204  assessments depending on the SDLT disease.  
205   
206    If the ASO drug product administration is discontinued for safety or other reasons, the 
207  sponsor should continue safety monitoring of the trial participant until resolution of the 
208  adverse event(s) and evaluate the trial participant for potential late-onset toxicities.  
209   
210  F.  Assessment of Clinical Response 
211   
212  Sponsors should consider the following recommendations for assessing participants clinical 
213  response to investigational ASO drug products and outline in the IND submission a plan for 
214  evaluation of clinical benefit in relation to observed toxicities (as applicable): 
215   
216    The assessment of whether the ASO drug product is providing clinical benefit to the 
217  participant is an important element of the overall clinical assessment throughout the 
218  administration period. To best inform decisions regarding continuation of administration, 
219  sponsors should carefully track clinical changes over time with a specific plan for 
220  adjustment of the dosing regimen to achieve a desirable clinical response. The protocol 
221  should clearly outline the specific method(s) and timing of clinical assessments.   
222   
223    Sponsors can use clinical assessments to follow important disease symptoms during 
224  administration of the ASO drug product. Examples include clinical outcome assessment 
225  scales, performance-based assessments, or trial participant- or caregiver-reported changes 
226  in symptoms. Clinical assessments of response to the investigational ASO drug product 
227  will depend on the trial participants signs and symptoms before administration of the 
228  ASO drug product and on the underlying disease, including the stage and severity of the 
229  disease at time of initiation of the investigational ASO drug product. The sponsor should 
230  administer these assessments at specified intervals determined by the disease 
231  pathophysiology as well as the PK and PD characteristics of the ASO drug product, and 
232  these assessments should be detailed in the IND submission. 
233   
234    PD biomarkers (laboratory, imaging, or others) that are scientifically justified and 
235  relevant to the target disease may help to assess response to the ASO drug product. The 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
236  protocol should clearly outline those assessments, and sponsors should carefully consider 
237  potential assay/method validation issues that may affect the results and data 
238  interpretation.  
239   
240    The protocol should have a prespecified plan for continually assessing the trial 
241  participants clinical response to the investigational ASO drug product to ensure that the 
242  benefit-risk assessment remains favorable to justify continued administration. Sponsors 
243  should consider discontinuing administration if there is no or inadequate clinical response 
244  or if the observed toxicities from the product outweigh the observed clinical benefits. 
  7