Acute Radiation 
Syndrome: Developing 
Drugs for Prevention 
and Treatment  
Guidance for Industry 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Ronald Honchel at 301-796-0915. 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
April 2023 
Animal Rule 
17074dft.docx 
04/12/23   
Acute Radiation 
Syndrome: Developing 
Drugs for Prevention 
and Treatment  
Guidance for Industry 
 
 
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) 
 
April 2023 
Animal Rule
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  DEVELOPMENT PROGRAM ............................................................................2 
A.  Overview of Drug Development ....................................................................................... 2 
B.  Early Drug Development .................................................................................................. 5 
1. Selection of Doses for Development .................................................................................... 6 
2. Drug Development Plan ...................................................................................................... 6 
C.  CMC ................................................................................................................................... 8 
D.  Establishing Efficacy in Animals ..................................................................................... 9 
E.  Efficacy Endpoints .......................................................................................................... 10 
F.  Clinical Safety Studies ..................................................................................................... 12 
G.  Requirement for Postmarketing Evaluation ................................................................. 12 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Acute Radiation Syndrome: 
2  Developing Drugs for Prevention and Treatment  
3  Guidance for Industry1 
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 provides information and recommendations to assist sponsors and other interested 
18  parties in the development of drugs2 to prevent or treat acute radiation syndrome (ARS) caused 
19  by exposure to ionizing radiation from accidental or deliberate events.  Generally, drugs 
20  developed for such indications will require approval under the regulations commonly referred to 
21  as the Animal Rule.3 
22   
23  This guidance is not intended to address the development of drugs to prevent or treat conditions 
24  that are the result of a downstream effect of the acute sequelae of exposure to ionizing radiation 
25  or secondary conditions in the setting of ARS (e.g., sepsis secondary to radiation injury to the 
26  gastrointestinal (GI) tract).  Furthermore, this guidance does not address delayed effects of acute 
27  radiation exposure (e.g., radiation-induced lung injury) or decorporation agents.4  
28  The general principles expressed in this guidance are based on the guidance for industry Product 
29  Development Under the Animal Rule (October 2015) (hereafter referred to as the Animal Rule 
 
1 This guidance has been prepared by the Divisions of Imaging and Radiation Medicine and Pharmacology-
Toxicology in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. 
 
2 As used in this guidance, the terms drugs or drug products refer to human drugs and therapeutic biological 
products regulated by CDER, unless otherwise specified.  In addition, the term approval refers to approval or 
licensure, unless otherwise specified. 
 
3 The Animal Rule provides a pathway for approval of drug or biological products when human efficacy studies are 
not ethical or feasible (see 21 CFR 314.600 through 314.650 for drugs or 21 CFR 601.90 through 601.95 for 
biological products).  Additional information about the Animal Rule is available at https://www.fda.gov/emergency-
preparedness-and-response/mcm-regulatory-science/animal-rule-information. 
 
4 For information on decorporation agents, see the guidance for industry Internal Radioactive Contamination  
Development of Decorporation Agents (March 2006).  We update guidances periodically.  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. 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
30  guidance).  Developing products under the Animal Rule can be very challenging.  Establishing 
31  early and ongoing communication with the review division is critical for a successful outcome. 
32   
33  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
34  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
35  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
36  the word should in Agency guidances means that something is suggested or recommended, but 
37  not required. 
38   
39   
40  II.  BACKGROUND 
41   
42  ARS is the term applied to a variety of clinical manifestations resulting from the exposure of 
43  humans to high doses of radiation.  The Centers for Disease Control and Prevention (CDC) 
44  defines ARS as an acute illness caused by irradiation of the entire body (or most of the body) by 
45  a high dose of penetrating radiation in a very short period of time (usually a matter of 
46  minutes).5  CDC further describes three classic ARS subsyndromes as hematopoietic syndrome 
47  (H-ARS), gastrointestinal syndrome (GI-ARS), and cardiovascular/central nervous system 
48  syndrome.  ARS usually will be accompanied by some skin damage.  The predominance of 
49  expression of these clinical subsyndromes is highly dependent on the magnitude and extent of 
50  radiation exposure and the time following exposure.   
51   
52   
53  III.  DEVELOPMENT PROGRAM 
54   
55  A.  Overview of Drug Development 
56   
57  For a drug product to be approved by FDA, a sponsor must provide substantial evidence6,7 that 
58  the drug has the effect it purports to have under the conditions of use described in the proposed 
59  labeling and that the drugs benefits outweigh its risks.  Generally, the evidence is derived from 
60  adequate and well-controlled clinical studies.  Human challenge studies (i.e., exposing volunteers 
61  to acute, high doses of ionizing radiation to study the effects of the drug) are not ethical and field 
62  trials are not feasible when developing drugs for ARS.  Under such circumstances, FDA may 
63  grant approval under the Animal Rule, based on adequate and well-controlled animal efficacy 
64  studies, when the results of those studies establish that the drug is reasonably likely to produce 
65  clinical benefit in humans.  However, it is important to note that under the Animal Rule, human 
66  studies are still required to demonstrate a drugs safety.8   
67   
 
5 See Acute Radiation Syndrome: A Fact Sheet for Clinicians, available at 
https://www.cdc.gov/nceh/radiation/emergencies/arsphysicianfactsheet.htm. 
 
6 The FD&C Act section 505(d) (21 U.S.C. 355(d)). 
 
7 The Public Health Service Act section 351 (42 U.S.C. 262). 
 
8 21 CFR 314.600 and 314.610(a) for drugs and 21 CFR 601.90 and 601.91(a) for biological products. 
2  Contains Nonbinding Recommendations 
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68  In some circumstances, efficacy studies conducted in humans with the investigational drug for 
69  conditions with pathophysiology similar to that of ARS may provide confirmatory evidence for 
70  approval.  For leukocyte growth factor (LGF) and thrombopoietin receptor agonist drugs 
71  approved for use in H-ARS, examples of confirmatory evidence include efficacy studies in 
72  subjects with cancer receiving myelosuppressive chemotherapy or myeloablative regimens 
73  before bone marrow transplantation and studies in subjects with immune thrombocytopenia who 
74  have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. 
75   
76  Improving capabilities for addressing radiological and nuclear emergencies is a national 
77  priority.9  FDA has developed distinct approaches to facilitate and expedite development and 
78  review of new drugs to address unmet medical needs for treating serious or life-threatening 
79  conditions.10  Drugs developed for ARS may be eligible for certain FDA expedited programs 
80  (e.g., fast track and priority review) or other FDA programs (e.g., orphan drug designation).11  
81  Sponsors requesting these designations should use established procedures.12  Breakthrough 
82  therapy designation requires preliminary clinical evidence demonstrating that the drug may have 
83  substantial improvement on at least one clinically significant endpoint over available therapy.13, 
84  Drugs being developed under the Animal Rule might meet the statutory requirement for 
85  breakthrough therapy designation when there is such preliminary clinical evidence in a condition 
86  closely related to the indication sought under the Animal Rule.  For example, clinical evidence in 
87  chemotherapy-induced myelosuppression might support breakthrough therapy designation for 
88  ARS-associated myelosuppression.  
89   
90  Developing the animal models in which to test the efficacy of investigational products being 
91  developed under the Animal Rule is challenging.  Animal models should reflect the clinical 
92  condition for which the drug is being developed (e.g., H-ARS or GI-ARS).  The Animal Rule 
93  guidance defines animal model as a specific combination of an animal species, challenge agent, 
94  and route of exposure that produces a disease process or pathological condition that in multiple 
95  important aspects corresponds to the human disease or condition of interest.14  Given the 
96  multisystem nature of ARS, radiation exposure directed at sections of the body (e.g., thoracic or 
97  abdominal region) may be of limited value for confirmatory studies.  Therefore, total-body 
 
9 See Radiological and Nuclear Emergency Preparedness Information from FDA, available at 
https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/radiological-and-nuclear-emergency-
preparedness-information-fda. 
 
10 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014). 
 
11 Information on orphan drug designation is available at https://www.fda.gov/industry/medical-products-rare-
diseases-and-conditions/designating-orphan-product-drugs-and-biological-products. 
 
12 See Appendix 1, Processes for Fast Track, Breakthrough Therapy, and Priority Review Designations, in the 
guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics. 
 
13 See section 506 of the FD&C Act (21 U.S.C. 356) (as amended by the Food and Drug Administration Safety and 
Innovation Act, Public Law 112-144).  See also section VI. A, Qualifying Criteria for Breakthrough Therapy 
Designation, in the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics. 
 
14 See the guidance for industry Product Development Under the Animal Rule (October 2015). 
 
3  Contains Nonbinding Recommendations 
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98  irradiation with or without partial bone marrow sparing (e.g., 2.5 percent or 5 percent) is 
99  recommended in the animal studies.  Sponsors should conduct the efficacy studies in a manner 
100  consistent with the ethical use of animals and use the minimum number of animals necessary to 
101  ensure scientifically valid results.15 
102   
103  Sponsors should consider factors such as age and sex, which may contribute to differences in the 
104  responses to drugs being developed under the Animal Rule to treat or prevent ARS.  Sponsors 
105  should discuss with the review division how they intend to address the effects of demographic 
106  factors such as age and sex on the susceptibility to radiation and the response of their 
107  investigational drug in animal models.  In general, efficacy studies in juvenile animals are not 
108  required because efficacy can be extrapolated from adult animals and 
109  pharmacokinetic/pharmacodynamic (PK/PD) data to determine dosing in pediatric patients.  
110  Sponsors are required to submit an initial pediatric study plan16 to their investigational new drug 
111  application (IND) no later than 60 calendar days after the date of the end-of-phase 2 meeting 
112  unless the drug has been granted orphan designation for the proposed ARS indication.17  Sex-
113  specific differences in the susceptibility to radiation-induced injury occur in animal models of 
114  ARS resulting in differences in mortality and in physiological responses to radiation.  However, 
115  sex-specific differences in response to approved treatments have not been identified.  It is 
116  important to determine whether sex-based differences in animal models of ARS are associated 
117  with differential response to an investigational treatment. 
118   
119  The Agency encourages sponsors to establish early and ongoing communication to develop a 
120  drug development plan that will support the proposed indication (e.g., anticipated clinical use, 
121  dosing regimen, and route of administration).  The approved ARS indication will generally 
122  include the subsyndrome or organ system that is affected by the radiation and mitigated by the 
123  therapy and the nature of the benefit observed in the animal efficacy studies, typically increased 
124  survival or prevention of major morbidity.  The mechanism of action of the drug must be 
125  reasonably well-understood for approval under the Animal Rule18 and must be described in the 
126  product labeling.19  For example, certain hematopoietic growth factor or thrombopoietin receptor 
127  agonist products stimulate the proliferation and differentiation of progenitor cells in the bone 
128  marrow and increase recovery of progenitor cells and survival of animals after myelosuppressive 
129  doses of radiation.  Growth factors targeting different progenitor cells in other organs might 
 
15 Approval under the Animal Rule requires adequate and well-controlled animal efficacy studies; however, we 
support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible.  We encourage 
sponsors to consult with FDA if 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.  See also https://www.fda.gov/science-research/about-science-research-fda/advancing-
alternative-methods-fda. 
 
16 See section 505B(e)(2) of the FD&C Act (21 U.S.C. 355c). 
 
17 See section 505B(k)(1) of the FD&C Act (21 U.S.C. 355c).  See also the guidance for industry Pediatric Study 
Plans:  Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study 
Plans (July 2020). 
 
18 21 CFR 314.610(a) for drugs and 21 CFR 601.91(a) for biological products. 
 
19 21 CFR 201.57(c)(13)(i)(A). 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
130  increase survival by, for example, promoting recovery of gastrointestinal mucosa in GI-ARS.  A 
131  broad indication for increase in survival agnostic of organ system may be based upon evidence 
132  of improved survival attributable to any one of several mechanisms of drug action, such as 
133  enhancing the recovery of the multiorgan injury of ARS (e.g., modulators of immune responses 
134  or of programmed cell death). 
135   
136  Design considerations for animal efficacy studies would be different for a drug for prophylaxis 
137  compared with a drug for treatment.  Pre-exposure prophylaxis studies should be designed to 
138  determine the likely time course of the prophylactic effect (i.e., the minimum time the subject 
139  must wait after taking the drug before radiation exposure) and how long the prophylactic effect 
140  lasts.  Study design should also incorporate standard of care for postradiation exposure treatment, 
141  including the potential concurrent use of LGFs, for example. 
142   
143  A product being developed for ARS may be considered for use under an emergency use 
144  authorization or under an expanded access mechanism.  An emergency use authorization is a 
145  regulatory mechanism by which, under certain emergency circumstances and when a requisite 
146  declaration under section 564(b) of the FD&C Act is in place, the FDA Commissioner may 
147  authorize the use of unapproved medical products or the unapproved use of approved medical 
148  products to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by 
149  a chemical, biological, radiological, or nuclear threat agent that is the subject of such declaration, 
150  when, among other criteria, there are no adequate, approved, and available alternatives.20  
151  Expanded access is a potential pathway for a patient with an immediately life-threatening 
152  condition or serious disease or condition to gain access to an investigational drug product for 
153  treatment outside of clinical trials when no comparable or satisfactory alternative therapy options 
154  are available.21   
155   
156  B.  Early Drug Development 
157   
158  Sponsors typically request a pre-IND meeting with the review division when they have 
159  information on chemistry, manufacturing, and controls (CMC), the mechanism of action, 
160  proposed use, nonclinical proof-of-concept or clinical data from a related indication that provides 
161  support for the mechanism of action, and an overall strategy for nonclinical and clinical 
162  development of the investigational drug.  Sponsors may request a pre-IND meeting at earlier 
163  stages of product development if needed.  The appropriateness of the proposed animal models is 
164  an important topic for discussion at this meeting.  Efficacy studies in nonhuman primates (NHPs) 
165  are not required to support either a pre-IND meeting request or the filing of an IND.  Exploratory 
166  efficacy studies may be conducted in any acceptable (e.g., agreed-upon, pharmacologically 
167  relevant) species.  
168   
 
20 For more information on emergency use authorizations, please see the guidance for industry and other 
stakeholders Emergency Use Authorization of Medical Products and Related Authorities (January 2017).   
 
21 For more information on expanded access mechanisms, see https://www.fda.gov/news-events/expanded-
access/expanded-access-information-industry. 
 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
169  Pre-IND meetings with the review division are particularly important for product development 
170  under the Animal Rule.  Pre-IND meetings are useful to prevent unnecessary studies, to increase 
171  the likelihood that needed studies will provide useful information, and to allow a discussion of 
172  scientific ideas and exchange of information and experience.22  The review division will work 
173  with sponsors to clarify their best path forward, including the most appropriate animal models, 
174  primary endpoints for efficacy studies, and PD endpoints to support dose translation.  FDA 
175  recognizes that, in some instances, a series of meetings23 (such as Type C meetings) rather than 
176  only a single meeting might be required in the pre-IND stage.  
177   
178  1.  Selection of Doses for Development 
179   
180  For selection of a human dose based on a PD marker, the PD marker should be shown in animals 
181  and humans to correlate with the mechanism of action by which the drug prevents or 
182  substantially reduces the radiation-induced condition and with the desired clinical outcome (i.e., 
183  enhancement of survival or prevention of major morbidity).  In addition, human PK/PD studies 
184  should support a human drug dose that would result in PD marker levels in the desired range that 
185  is predictive of marker levels associated with efficacy in the adequate and well-controlled animal 
186  studies.  The PD marker and its assay methods and performance characteristics in the animal 
187  species and in humans should be described and agreed upon with FDA. 
188   
189  In the absence of an accepted PD marker, an approach for dose selection for systemically 
190  absorbed drugs should be based on a comparison of relevant exposure parameters in the animal 
191  species and humans.24 
192   
193  2.  Drug Development Plan 
194   
195  The following is a potential sequence for conducting animal and human studies to support a 
196  marketing application for an ARS drug under the Animal Rule:  
197   
198    Preclinical evaluation of drug pharmacology (e.g., potency against target, selectivity) and 
199  toxicity.  
200   
201    Natural history studies to characterize and select animal models that are intended to be 
202  translational or candidate models as adequate and well-controlled studies under the 
203  Animal Rule.  Selected animal models should adequately reflect the radiation-induced 
204  injury in humans, including the time course and manifestations of the injury.  In addition, 
 
22 Pre-IND/IND information is available at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati
ons/InvestigationalNewDrugINDApplication/default.htm. 
 
23 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products (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. 
 
24 For a detailed discussion, see section V. B, Elements Related to the Investigational Drug and the Selection of an 
Effective Dose in Humans, in the Animal Rule guidance.   
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205  the pharmacology of the drug (e.g., the pathophysiological role and tissue distribution of 
206  the molecular target of the drug) should be generally similar in the animal models and in 
207  humans. 
208   
209    Exploratory animal efficacy studies conducted in relevant animal models. 
210   
211    PK studies, conducted in relevant animal models, ideally employing a range of drug 
212  doses to support selection of the human dose and regimen. 
213   
214    Animal safety pharmacology and toxicology studies. 
215   
216    Single dose (and multiple doses, if needed), dose-escalation, safety, and PK studies in 
217  healthy humans using doses that are appropriately safe based upon toxicology studies and 
218  have appropriate PD activity based upon exploratory animal studies.  
219   
220    Adequate and well-controlled animal efficacy studies conducted in the agreed-upon 
221  animal models as well as PK and/or PD studies in those species necessary to support the 
222  human dose selection (e.g., dose-finding studies necessary for understanding the 
223  exposure/response relationship in the proposed animal models). 
224   
225    Additional human safety studies to provide an adequate safety database (see section F). 
226   
227  Under the Animal Rule, the nonclinical studies needed to support human safety trials are the 
228  same as those required under traditional drug development with the expectation that nonclinical 
229  safety and toxicity studies generally should be conducted under good laboratory practice (GLP) 
230  regulations (21 CFR part 58).25   
231   
232  There are no regulations that specifically address data quality and integrity issues for the 
233  adequate and well-controlled animal efficacy studies and the PK and/or PD studies in animals 
234  used to select a dose and regimen for humans (i.e., dose conversion studies); however, FDA 
235  recommends following GLP regulations to the extent practicable.  The Agency recognizes the 
236  technical and practical challenges in conducting studies in irradiated animals, and there may be 
237  justifiable limitations in the ability to apply the GLP regulations when conducting these studies.   
238   
239  Before initiating these studies, sponsors should identify aspects of the studies anticipated to be a 
240  challenge regarding the GLP regulations and propose methods for adapting the studies to ensure 
241  the quality and integrity of the resulting data.  Sponsors should seek concurrence from the review 
242  division on the data quality and integrity plan before initiating studies.26  There may be other 
243  nonclinical studies for which the review division may recommend using GLP regulations, to the 
 
25 For further information about these nonclinical studies, see the ICH guidances for industry M3(R2) Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (January 
2010) and S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (May 2012). 
 
26 For a detailed discussion, see section IV. B, Study Conduct, in the Animal Rule guidance. 
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244  extent practicable.  If there is any question about whether any nonclinical study should be 
245  conducted under GLP, sponsors should consult the review division. 
246   
247  C.  CMC 
248   
249  A sufficiently characterized drug is critical to relate the drug used in Animal Rulespecific 
250  nonclinical studies to the drug proposed for use in human studies.  Sponsors should perform the 
251  adequate and well-controlled animal efficacy studies intended to support approval and human 
252  safety studies using the to-be-marketed drug formulation.  Any differences between the 
253  formulation used and the to-be-marketed formulation should be discussed with the review 
254  division before studies are initiated.  If the animal model used makes dosing with the to-be-
255  marketed human drug formulation difficult, sponsors should administer the drug to the animals 
256  using a dosing regimen that would provide drug exposures comparable to those in humans.   
257   
258  Sufficient CMC characterization is necessary for the adequate and well-controlled animal 
259  efficacy studies that provide the primary evidence of effectiveness for approval under the Animal 
260  Rule and for the PK and/or PD studies that are used to select the drug dose and regimen in 
261  humans.27  
262   
263  Drugs, as defined under section 201(g) of the Federal Food, Drug, and Cosmetic Act (FD&C 
264  Act), contain active ingredients and may contain inactive ingredients.  As such, study drug 
265  ingredients are required to be produced at facilities that comply with current good manufacturing 
266  practice (CGMP) requirements under section 501(a)(2)(B) of the FD&C Act.28  When an IND is 
267  submitted, regulations under 21 CFR 312.23(a)(7) require including the CMC section in the IND 
268  describing the composition, manufacture, and control of the drug substance and the drug product.  
269  This information is necessary to ensure the proper identification, quality, purity, and strength of 
270  the investigational drug.  The amount of information needed to make that assurance will vary 
271  with the phase of the investigation, the proposed formulation, and duration of the investigation.29   
272   
273  For the preparation of the CMC section of an IND, refer to the guidance for industry Content and 
274  Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, 
275  Including Well-Characterized, Therapeutic, Biotechnology-derived Products (November 1995), 
276  which contains guidance on the format and the content of the CMC section of the IND.  For 
277  recommendations regarding CMC requirements at the stage of the adequate and well-controlled 
278  animal efficacy studies, refer to the guidance for industry INDs for Phase 2 and Phase 3 Studies 
279  Chemistry, Manufacturing, and Controls Information (May 2003).   
280   
 
27 21 CFR 312.23(a)(7). 
 
28 According to the guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical 
Ingredients (September 2016), CGMP controls should be implemented after the designation of starting materials. 
 
29 21 CFR 312.23(a)(7).  For CMC information included in IND applications, please see also the following FDA 
website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati
ons/InvestigationalNewDrugINDApplication/ucm362283.htm. 
 
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281  The approach to producing investigational drugs in compliance with CGMP requirements may 
282  vary based on the phase of the clinical trial.  The FDA guidance for industry CGMP for Phase 1 
283  Investigational Drugs (July 2008) provides more information on this topic.  Investigational drugs 
284  must comply with the statutory requirements for CGMP under section 501(a)(2)(B) of the FD&C 
285  Act.   
286   
287  D.  Establishing Efficacy in Animals 
288   
289  Studies should be conducted to establish a lethality profile and define the radiation dose-response 
290  relationship in the selected species (and strain or substrain when relevant) and include periods of 
291  observation appropriate for the ARS subsyndrome and species.  The dose-response curve 
292  generated should be compared with curves from studies of similar design reported in the 
293  scientific literature.  Sponsors should explain any important differences.  FDA recommends that 
294  each testing facility confirm the reproducibility of its dose-response curves periodically and as 
295  necessary (e.g., if there are major changes in standard operating procedures). 
296   
297  Various radiation sources and types may be used in nonclinical studies.  The metric of biological 
298  effect (e.g., LD , or lethal dose sufficient to kill 50 percent of irradiated animals within 60 
50/60
299  days) can be attained through controlled irradiation conditions irrespective of radiation source or 
300  radiation type.  Sponsors should provide a detailed justification for the source and type of 
301  radiation, the dose or doses to be used in a study, how the animals would be irradiated, and the 
302  relevance to the intended clinical conditions of use.  A determination of dose modification factor 
303  (i.e., a demonstration that the mortality caused by various radiation doses in treated animals can 
304  be matched at any level of radiation by a constant fraction of the radiation dose in untreated 
305  animals) is not required.  For the adequate and well-controlled animal efficacy studies, FDA 
306  generally considers demonstration of efficacy against the effects of a single dose level of 
307  radiation to be sufficient (e.g., animals exposed to a single dose of 10 Gy); however, there may 
308  be circumstances for which FDA would recommend that a sponsor test its investigational drug 
309  against the effects of a range of dose levels of radiation (e.g., animals exposed to a single dose of 
310  7.0, 8.5, or 10 Gy). 
311   
312  The Agency recommends that sponsors standardize and document the time of day that each 
313  animal is irradiated given the potential impact of circadian rhythms on responses to 
314  irradiation.30,31 
315   
316  Regarding the number of animal species studied to demonstrate a drugs treatment effect, the 
317  Animal Rule requires that the effect is demonstrated in more than one animal species expected 
318  to react with a response predictive for humans, unless the effect is demonstrated in a single 
319  animal species that represents a sufficiently well-characterized animal model for predicting the 
 
30 Williams, JP, SL Brown, GE Georges, M Hauer-Jensen, RP Hill, AK Huser, DG Kirsch, TJ MacVittie, KA 
Mason, MM Medhora, JE Moulder, P Okunieff, MF Otterson, ME Robbins, JB Smathers, and WH McBride, 2010, 
Animal Models for Medical Countermeasures to Radiation Exposure, Radiat Res, 173(4):557578. 
 
31 Plett, PA, CH Sampson, HL Chua, M Joshi, C Booth, A Gough, CS Johnson, BP Katz, AM Farese, J Parker, TJ 
MacVittie, and CM Orschell, 2012, Establishing a Murine Model of the Hematopoietic Syndrome of the Acute 
Radiation Syndrome, Health Phys, 103(4):343355. 
 
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320  response in humans.32  Decisions about the adequacy of a single model are made by the Agency 
321  on a case-by-case basis after considering all available data to determine how well the single-
322  animal model represents the clinical condition and how translational the model is expected to be.  
323  Factors to be considered in determining the adequacy of the animal model or models include the 
324  ARS manifestations and time course in animals versus humans, the similarities and differences in 
325  the pathophysiology of the radiation-induced condition between animals and humans, the 
326  pharmacology of the target of the investigational drug in animal species relative to humans, and 
327  the PD/efficacy relationship in animals relative to the PD response in humans.  Confirmatory 
328  evidence of efficacy might be derived from data in a somewhat similar human condition.    
329   
330  The Animal Rule states: In assessing the sufficiency of animal data, the agency may take into 
331  account other data, including human data, available to the agency.33  For example, the Agency 
332  determined that efficacy demonstrated in the rhesus macaque model used for the H-ARS 
333  indication for filgrastim and other LGFs is acceptable because of the available human efficacy 
334  data in patients with myelosuppression or myeloablation attributable to cancer therapy or 
335  accidental radiation exposure who were treated with LGFs. 
336   
337  When a drug is pharmacologically active only in humans and is intended to address an unmet 
338  medical need for ARS, the use of a surrogate drug that achieves the engagement of the 
339  pharmacological target in animals may be considered for the animal efficacy studies.  In such 
340  circumstances, it is strongly recommended that sponsors meet with the review division to 
341  determine the adequacy of a surrogate drug for the adequate and well-controlled efficacy studies. 
342   
343  It is important to ensure the humane care and use of the laboratory animals to minimize distress 
344  and pain and to provide nutritional and fluid support.  Supportive care, as defined in the Animal 
345  Rule guidance, is needed only to mimic, to the extent possible, the human clinical scenario.  If 
346  the expected clinical scenario is to use the drug in a mass-casualty situation in which supportive 
347  care is not immediately available, the adequate and well-controlled animal efficacy studies 
348  necessary for approval may be conducted with adequate veterinary care necessary to minimize 
349  pain and suffering.  Alternatively, if the expected clinical setting is to use the drug in a situation 
350  in which supportive care is available, FDA recommends that sponsors propose and justify a 
351  supportive care regimen that will mimic the proposed use of the product.  Sponsors should 
352  discuss all animal care interventions with the review division.34 
353   
354  E.  Efficacy Endpoints 
355   
356  Generally, drugs for ARS are developed under the Animal Rule because human challenge studies 
357  are not ethical and field trials are not feasible.  In addition, the demonstration of effectiveness of 
358  a drug in a related condition of use (e.g., in myelosuppression induced by cancer therapies or in 
 
32 21 CFR 314.610(a)(2) for drugs and 21 CFR 601.91(a)(2) for biological products. 
 
33 21 CFR 314.610(a) for drugs and 21 CFR 601.91(a) for biological products. 
 
34 See Section IV. C. and Appendix B in the Animal Rule guidance. 
 
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359  immune-mediated cytopenia) generally cannot be fully extrapolated to ARS because these 
360  conditions do not adequately reflect the ARS pathophysiology. 
361   
362  For each of the drugs approved for H-ARS to date (i.e., LGFs: filgrastim, pegfilgrastim, and 
363  sargramostim; and thrombopoietin receptor agonist: romiplostim), a single animal efficacy study 
364  in a single NHP model of H-ARS was required to provide substantial evidence of effectiveness, 
365  estimate the treatment effect, and establish a dose and regimen for humans.  The adequate and 
366  well-controlled animal efficacy studies demonstrated an increase in survival at a prespecified 
367  time point posttreatment (the prospectively defined primary endpoint) accompanied by the 
368  supportive evidence of the expected pharmacological effect (i.e., resolution of neutropenia or 
369  thrombocytopenia); therefore, the studies were relied on for approval.  For each of the drugs 
370  discussed, the results of the adequate and well-controlled efficacy study were supported by 
371  existing human efficacy data from relevant approved indications.   
372   
373  Generally, enhancing survival or preventing major morbidity should be the primary endpoint in 
374  animal efficacy studies.35  In addition to improved survival, endpoints reflecting reduction in 
375  important ARS complications or prevention of major morbidity, such as fewer major 
376  hemorrhages, needed transfusions, or serious infections, may also be acceptable as primary 
377  efficacy outcomes.  For a survival benefit, overall survival at a relevant time point (e.g., when 
378  the proportion of animals surviving has plateaued), rather than only reduction in time to death 
379  without any difference in the proportion of animals that ultimately survive, should be 
380  demonstrated.  The timing of assessing the primary endpoint should be based upon natural 
381  history studies.  Typically, survival should be evaluated for 30 days for rodents and 60 days for 
382  nonrodents, given that their Kaplan-Meier survival curves after radiation exposure plateau at 
383  these time points in these animals.  PD endpoints, such as a favorable effect on neutropenia in an 
384  efficacy study of an LGF, are useful in supporting the mechanism of action of the drug and for 
385  selecting an effective dose and regimen in humans and are considered secondary efficacy 
386  endpoints.  Sponsors are strongly encouraged to discuss potential efficacy endpoints in animal 
387  studies with the review division before starting the study.   
388   
389  GI-ARS generally occurs after exposure to a much greater radiation dose than H-ARS (e.g., 
390  LD  of 11.33 Gy for GI-ARS versus LD  of 7.54 Gy for H-ARS in NHP total-body 
50/15 50/60
391  irradiation models).36  Therefore, even when GI-ARS is the intended target for therapy, the 
392  animal models and the efficacy outcomes should consider the manifestations of H-ARS.  For 
393  example, improvement in survival at 10 to 15 days in an animal model of GI-ARS will provide 
394  useful information on a drugs activity in exploratory, proof-of-concept studies before lethality 
395  attributable to H-ARS ensues.  To provide substantial evidence of effectiveness of an 
396  investigational drug for the treatment of GI-ARS, it is important to study the effect of the drug on 
397  overall survival and safety assessed at a time point defined by natural history studies of radiation 
398  doses that induce GI-ARS (e.g., 30 and 60 days, respectively, in rodents and NHPs).  For this 
399  objective, a clinically relevant animal model might consist of a total-body irradiation model with 
 
35 See 21 CFR 314.610(a)(3) for drugs and 21 CFR 601.91(a)(3) for biological products. 
 
36 Farese, AM, AW Bennett, AM Gibbs, KG Hankey, K Prado, W Jackson, III, and TJ MacVittie, 2019, Efficacy of 
Neulasta or Neupogen on H- and GI-ARS Mortality and Hematopoietic Recovery in Nonhuman Primates After 10 
Gy Irradiation With 2.5% Bone Marrow Sparing. Health Phys, 116(3):339353. 
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400  partial bone marrow sparing and supportive therapy that permit recovery from H-ARS as well as 
401  evaluation of the investigational drug efficacy based on survival from GI-ARS injury.  
402  Acceptable secondary efficacy endpoints may include assessment of GI function (e.g., 
403  malabsorption, body weight loss, mucosal barrier function, diarrhea, dehydration, vomiting) and 
404  structure (e.g., histopathologic assessment of viable crypts, apoptotic cells, and villus height). 
405   
406  F.  Clinical Safety Studies 
407   
408  Certain investigational drugs under development for treating ARS might be associated with 
409  severe adverse reactions that preclude a full characterization of the drugs safety in healthy adult 
410  volunteers.  The Agency will not rely primarily on nonclinical information to assess safety; 
411  approval of a new drug requires an adequate human safety database, regardless of the regulatory 
412  development pathway.37,38  If nonclinical or clinical data raise safety concerns about further 
413  testing of the investigational drug in healthy adult volunteers, sponsors should consider acquiring 
414  the needed human safety information in a patient population for which the drug offers a potential 
415  benefit that justifies the drugs risks.  Human safety data from a drug development program for 
416  which the drugs benefit-risk is appropriate could then be used to support the ARS indication.  
417  Sponsors should provide a justification for extrapolating to ARS the human safety data from the 
418  clinical condition chosen. 
419   
420  Because approval of drugs under the Animal Rule also requires an adequate human safety 
421  database, clinical safety data from previous clinical experience may be applicable.  For example, 
422  the safety of certain LGFs for use in H-ARS was extrapolated from the previously approved 
423  clinical uses in oncology indications.   
424   
425  G.  Requirement for Postmarketing Evaluation 
426   
427  The Animal Rule requires sponsors to conduct postmarketing studies to verify the drugs clinical 
428  benefit and to assess its safety when such studies are feasible and ethical and to include with the 
429  marketing application a plan or approach to conducting such a study.39  FDA recommends that 
430  an ARS study protocol be developed to specify collection of data (as feasible) for exploring 
431  covariates affecting survival such as age, estimated absorbed dose of radiation, ARS drug 
432  treatment, treatment dose, duration, and time to initiation of treatment after radiation exposure. 
433   
 
37 21 CFR 314.600 and 314.610(a) for drugs and 21 CFR 601.90 and 601.91(a) for biological products. 
 
38 See also 67 FR 37988 at 37989 (May 31, 2002). 
 
39 21 CFR 314.610(b)(1) for drugs and 21 CFR 601.91(b)(1) for biological products. 
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