Generally Accepted 
Scientific Knowledge in 
Applications for Drug and 
Biological Products:  
Nonclinical Information 
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DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only.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 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Office of Regulatory Policy, 301-
796-3601, or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 
240-402-8010.  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2023 
Pharmacology/Toxicology 
 
   
Generally Accepted 
Scientific Knowledge in 
Applications for Drug and 
Biological Products:  
Nonclinical Information 
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  
and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances     
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2023 
Pharmacology/Toxicology 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  Nonclinical Studies and Their Role in Drug Development ........................................................ 2 
B.  Legal and Regulatory Considerations .......................................................................................... 3 
III.  DISCUSSION .................................................................................................................... 3 
A.  GASK:  A General Description .................................................................................................... 4 
B.  Two Examples of GASK ................................................................................................................ 4 
1. Substances Typically Present in a Healthy Human Body ................................................................ 4 
2. GASK Regarding an Altered Biological Mechanism or Pathway ................................................... 5 
C.  Submission of GASK in Product Applications ............................................................................ 5 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Generally Accepted Scientific Knowledge in Applications for Drug 
2  and Biological Products:  Nonclinical Information 
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  FDA has received an increasing number of questions regarding the extent to which generally 
18  accepted scientific knowledge (GASK) may be relied on for drug or biological product 
19  approval.2  This guidance describes instances in which it may be appropriate to rely on GASK to 
20  meet certain nonclinical safety requirements for new drug applications (NDAs) submitted under 
21  section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)) and 
22  biologics license applications (BLAs) under section 351 of the Public Health Service Act (PHS 
23  Act) (42 U.S.C. 262(a)).  The information that supports the nonclinical safety of a drug and that 
24  must be submitted in the application can include references to GASK, when appropriate, instead 
25  of or in addition to, specific studies conducted with respect to the drug.  In such cases, therefore, 
26  it might be unnecessary to conduct certain nonclinical studies.3   
27   
28  This guidance focuses on two examples of GASK that could be appropriate to fulfill certain legal 
29  and regulatory requirements applicable to the drug or biological product in question.  The 
30  examples discussed in this guidance reflect areas where we have previously determined that it 
31  was appropriate to rely on GASK to meet certain requirements for approval.  Notably, while the 
32  examples provided here are for illustrative purposes, determinations regarding the 
33  appropriateness of data submitted for any application, including GASK, are fact-specific, and the 
34  question of whether certain information can be considered GASK and the purpose such 
35  information would serve in an application will be considered in the context of a particular 
36  application.   
37   
 
1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for 
Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA).  
2 For brevity for purposes of this guidance, the term drug, unless stated otherwise, is intended to refer to both drugs 
under the Federal Food, Drug, and Cosmetic Act and biological products under the Public Health Service Act; and 
the term approval is intended to refer to approval and licensure of drug and biological product applications under the 
respective authorities.   
3 This guidance does not address the use of GASK in other contexts (e.g., clinical studies). 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
38  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
39  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
40  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
41  the word should in Agency guidances means that something is suggested or recommended, but 
42  not required. 
43   
44   
45  II.  BACKGROUND 
46   
47  A.  Nonclinical Studies and Their Role in Drug Development 
48   
49  Applicants are required to submit, among other things, nonclinical information to support 
50  approval of an NDA or BLA (see, for example, parts 314 and 601 (21 CFR parts 314 and 601)).  
51  For example, the NDA regulations provide that NDAs include data about the drugs 
52  pharmacology and disposition (pharmacological effects, including mechanism(s) of action;4 
53  absorption, distribution, metabolism, excretion5) and toxicology (acute, subacute, and chronic 
54  toxicity;6 developmental and reproductive toxicity;7 carcinogenicity;8 and special toxicology, as 
55  appropriate9).  The NDA regulations note that these data can come from studies conducted in 
56  animals or in vitro.10 
57   
58  The nonclinical information described above addresses critical issues that allow the Agency to, 
59  for example: 
60   
61    Identify the pharmacological effects, including mechanism(s) of action of the drug in 
62  vitro and/or in vivo  
63   
64    Identify the absorption, distribution, metabolism, and excretion of the drug in vitro and/or 
65  in animals 
66   
67    Identify possible consequences of exposure duration (e.g., chronic) 
68   
69    Identify risks for special populations (e.g., pediatrics) 
 
4  314.50(d)(2)(i) (Studies of the pharmacological actions of the drug in relation to its proposed therapeutic 
indication and studies that otherwise define the pharmacologic properties of the drug or are pertinent to possible 
adverse effects.)  
5  314.50(d)(2)(iv) (Any studies of the absorption, distribution, metabolism, and excretion of the drug in 
animals.) 
6  314.50(d)(2)(ii) (Studies of the toxicological effects of the drug as they relate to the drug's intended clinical 
uses, including, as appropriate, studies assessing the drug's acute, subacute, and chronic toxicity . . ..) 
7  314.50(d)(2)(iii) (Studies, as appropriate, of the effects of the drug on reproduction and on the developing 
fetus.) 
8  314.50(d)(2)(ii) (Studies of the toxicological effects of the drug as they relate to the drug's intended clinical 
uses, including, as appropriate, . . . carcinogenicity . . . .) 
9  314.50(d)(2)(ii) (Studies of the toxicological effects of the drug as they relate to the drug's intended clinical 
uses, including, as appropriate, ... studies of toxicities related to the drug's particular mode of administration or 
conditions of use.) 
10 See, for example,  314.50(d)(2).  See also the BLA regulations at 21 CFR part 601, which are silent with respect 
to the source of nonclinical data. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
70    Identify specific parameters to inform safety in humans 
71   
72    Identify the mechanistic understanding of an adverse biological change observed in 
73  animals or humans 
74   
75  Relevant regulations do not specify the exact study types and designs needed to examine 
76  particular issues or determine particular outcomes.11  The studies recommended to address these 
77  issues are a matter of scientific and regulatory judgment, and are often described in FDA 
78  guidances and International Council for Harmonisation guidelines.  The guidances that discuss 
79  which studies may be appropriate in a given situation also provide flexibility, and alternative 
80  approaches to those recommended can be used if they satisfy the applicable statutes and 
81  regulations.  
82   
83  B.  Legal and Regulatory Considerations 
84   
85  Standalone marketing applications submitted under section 505(b)(1) of the FD&C Act or 
86  section 351(a) of the PHS Act must contain data sufficient to demonstrate the safety and 
87  effectiveness of the drug, or the safety, purity, and potency of the biological product, 
88  respectively.  As a general matter, applicants for standalone marketing applications rely on either 
89  their own data or data to which they have a right of reference.  A standalone applications 
90  nonclinical data (which, as discussed above, may be derived from in vitro or in vivo studies, as 
91  appropriate) thus generally come from two potential sources: studies conducted by the sponsor 
92  and studies not conducted by or for the sponsor but to which the sponsor has a right of reference.  
93  In some instances, such as in those circumstances described in this guidance with regard to 
94  nonclinical data, it may also be appropriate in a standalone marketing application to rely on 
95  information that is considered GASK to support approval without affecting the regulatory status 
96  of standalone marketing applications submitted under section 505(b)(1) of the FD&C Act or 
97  section 351(a) of the PHS Act.  Similarly, marketing applications submitted under section 
98  505(b)(2) of the FD&C Act or section 351(k) of the PHS Act may rely on information that is 
99  considered GASK to support approval.  
100   
101   
102  III.  DISCUSSION 
103   
104  As discussed above, in most cases, nonclinical studies provide necessary information relevant to 
105  the determination of the safety and effectiveness of a drug, or the safety, purity, and potency of a 
106  biological product, to support approval of a marketing application.12  In some cases, however, 
107  what is already known, for example, about a drug, the patients condition, or a relevant 
108  biological process (i.e., the biological context in which a drug is expected to act) in a given 
109  patient population is sufficient to confidently predict the outcome of a given nonclinical study.  If 
110  there is GASK relevant to the application, it may be unnecessary for a sponsor to conduct certain 
111  nonclinical studies.  This may result in streamlined product development that avoids unnecessary 
112  animal testing, decreases a drugs development costs, and quickens the drugs time to approval 
113  and marketing  and thus, its availability to patients.   
 
11 See, for example,  314.50. 
12 See generally, 21 CFR part 312; and 21 CFR parts 314 and 601. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
114   
115  A.  GASK:  A General Description 
116   
117  For the purposes discussed in this guidance, the term GASK is used to refer to medical or 
118  scientific information that is generally accepted by experts qualified by scientific training and 
119  experience in the relevant field, including FDA experts.  Generally, GASK is based on widely 
120  accepted scientific principles that are typically long-standing.  In addition, it may also be 
121  possible for GASK to be based on a sufficiently large volume of scientific studies/information 
122  that would be applicable beyond the specific instances in which that information was developed.  
123     
124  For example, information derived from the study of anatomy and physiology, of the type 
125  traditionally learned as part of an advanced science or medical degree, might be considered 
126  GASK, in which case it could be relied upon to fulfill certain regulatory requirements that 
127  otherwise would be fulfilled through nonclinical studies.  In addition, many studies or multiple 
128  streams of information collectively may also provide a body of information sufficient to support 
129  GASK.  For example, GASK could be evidenced by submitting textbook excerpts that include 
130  basic scientific principles for which specific products are not cited as the source of the 
131  information.  If you have questions about the applicability of GASK to a particular application, 
132  contact the appropriate review division. 
133   
134  B.  Two Examples of GASK 
135   
136  This guidance describes two circumstances in which sponsors have relied on GASK in their 
137  product development programs to meet relevant approval requirements:  (1) where a product 
138  contains a substance (either naturally derived or synthesized) that occurs naturally in the body, 
139  and sponsors have relied on GASK regarding that substance and its known effect on biological 
140  processes instead of conducting certain nonclinical studies; and (2) where a sponsor has 
141  demonstrated a drugs impact on a particular biological pathway, and then relies on GASK 
142  regarding that impact to conclude that certain nonclinical studies are not necessary to support 
143  approval and labeling of the drug.   
144   
145  1.  Substances Typically Present in a Healthy Human Body 
146   
147  a.  Endogenous substances 
148   
149  Some drugs have as their active ingredient a substance that is naturally present in the human 
150  body  for example, in situations where the drug replaces a substance that should naturally be 
151  present but, for pathological reasons, a patient may lack sufficient amounts of the substance to 
152  enable proper functioning.  In those cases, where the drug is an unmodified13 endogenous 
153  substance and a patients exposure to the drug reflects the same level of exposure and 
154  distribution of the endogenous substance seen in a healthy individual, GASK regarding the safety 
155  of such a drug may be used to obviate the need for certain nonclinical data.   
156   
 
13 For substances that have been modified, contact the appropriate review division to discuss appropriate study or 
studies to support approval. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
157  We note that, for some endogenous substances, natural exposure to the substance may be 
158  cyclical, or may vary depending on biofeedback mechanisms.  When administration of a drug 
159  could result in a different pattern or amount of exposure than the endogenous pattern or amount 
160  (e.g., hormones), human pharmacokinetic studies would likely be recommended and certain 
161  toxicology studies may be warranted to support these differences.   
162   
163  b.  Exogenous substances present in the diet 
164   
165  For substances exogenous to the body that are nevertheless a part of a typical diet, exclusive of 
166  dietary supplements, it may be appropriate in some circumstances to rely on GASK to meet 
167  certain requirements for approval of applications.  In such cases, certain nonclinical studies may 
168  be unnecessary.  For such exogenous substances, when a patients clinical exposure to an 
169  unmodified14 food substance does not exceed typical levels of dietary exposure and the drug has 
170  an oral route of administration, GASK regarding safety of the unmodified substance as part of 
171  the diet may suffice to fulfill certain requirements for approval instead of nonclinical studies, as 
172  appropriate.  When a patients clinical exposure to the unmodified substance does not exceed 
173  typical levels of dietary exposure but the drug has a non-oral route of administration, route-
174  specific nonclinical studies may still be needed.  When drug exposure is in excess of typical 
175  dietary exposure, a full battery of nonclinical studies would likely be needed. 
176   
177  2.  GASK Regarding an Altered Biological Mechanism or Pathway 
178   
179  Some drugs have very distinct effects on well-known biological pathways, such that certain 
180  outcomes can be predicted once a sponsor has demonstrated the drugs effect on the biological 
181  pathway.  In some cases, a drug has either on- or off-target impacts on a biological pathway or 
182  molecular mechanism of action that is known to result in adverse effects at clinically relevant 
183  exposures based on the operation of the biological pathway.  Thus, it may be appropriate to rely 
184  on GASK regarding the impact of the pathway rather than to conduct specific pharmacology 
185  and/or toxicology studies intended to measure the impact of the pathway. 
186   
187  For example, if a sponsor demonstrates clearly that a drug inhibits angiogenesis, which is 
188  necessary for fetal development, FDA may accept a rationale that includes the use of GASK to 
189  fulfill certain requirements instead of requiring the sponsor to conduct certain reproductive 
190  toxicology studies.  In such cases, a drugs demonstrated (i.e., via appropriate studies) effect on 
191  angiogenesis, plus GASK regarding the need for angiogenesis in maintaining a pregnancy, may 
192  suffice to label the drug with a statement warning of adverse effects on embryofetal development 
193  for women who are or may become pregnant while taking the drug.  GASK in the nonclinical 
194  context has generally been used in circumstances in which the drug-related alteration in a 
195  pathway results in adverse effects.   
196   
197  C.  Submission of GASK in Product Applications  
198   
199  If a sponsor believes that certain information is GASK, the sponsor should submit their rationale 
200  to the review division as early as possible in product development to obtain feedback with 
 
14 For substances that have been modified, contact the appropriate review division to discuss appropriate study or 
studies to support approval.  
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
201  respect to the proposed regulatory strategy for approval.  The submission should include relevant 
202  evidence supporting GASK, including textbook excerpts and/or non-product-specific published 
203  literature. 
  6