Mpox: Development  
of Drugs and Biological 
Products 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Kimberly Struble at 301-796-1500.  
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2023 
Clinical/Medical 
52235375dft.docx 
1/5/2023   
Mpox: Development  
of Drugs and Biological 
Products 
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) 
 
January 2023 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Table of Contents 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  DRUG DEVELOPMENT PROGRAM CONSIDERATIONS ..................................... 2 
A.  Regulatory Considerations ............................................................................................................ 2 
B.  Pharmacology/Toxicology Considerations .................................................................................. 3 
C.  Virology Considerations ................................................................................................................ 4 
D.  Clinical Considerations ................................................................................................................. 6 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Mpox: Development of Drugs and Biological Products  
2  Guidance for Industry 
3   
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  I.  INTRODUCTION 
15   
16  FDA is issuing this guidance to support sponsors in their development of drugs1 for mpox. This 
17  guidance provides nonclinical, virology, and clinical considerations for mpox drug development 
18  programs, with a focus on recommendations to support initiation of clinical trials. Preventive 
19  vaccines are not addressed in this guidance. Development of preventative vaccines raise different 
20  and additional considerations, including those pertaining to subject selection, safety monitoring, 
21  and effectiveness evaluation. We encourage developers of preventative vaccines to contact the 
22  Office of Vaccines Research and Review in the Center for Biologics Evaluation and Research.  
23   
24  Monkeypox virus is in the Orthopoxvirus genus of the Poxviridae family and is biologically 
25  similar to variola virus (the causative agent of smallpox). Although FDA has approved drugs for 
26  the treatment of smallpox under regulations commonly referred to as the Animal Rule,2 this 
27  pathway is not applicable to drugs for mpox because researchers can design and implement 
28  clinical trials for mpox that are both ethical and feasible. The Animal Rule applies to the 
29  approval of drugs for serious or life-threatening conditions caused by exposure to lethal or 
30  permanently disabling toxic biological, chemical, radiological, or nuclear substances when it is 
31  not ethical to conduct definitive human efficacy studies and not feasible to conduct field trials to 
32  study the effectiveness of a drug after an accidental or hostile exposure.3 
33   
34  In general, FDAs guidance documents, including this guidance, do not establish legally 
35  enforceable responsibilities. Instead, guidances describe the Agencys current thinking on a topic 
 
1 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified. 
 
2 21 CFR 314, subpart I (for drugs) and 21 CFR 601, subpart H (for biological products). 
 
3 See 21 CFR 314.600, 21 CFR 601.90, the guidance for industry Product Development Under the Animal Rule 
(October 2015), and the Animal Rule Information web page at https://www.fda.gov/emergency-preparedness-and-
response/mcm-regulatory-science/animal-rule-information. 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. For further discussion, see Sherwat, A et al., 2022, Tecovirimat and 
the Treatment of Monkeypox  Past, Present, and Future Considerations, N Engl J Med, 387:579581. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
36  and should be viewed only as recommendations, unless specific regulatory or statutory 
37  requirements are cited. The use of the word should in Agency guidance means that something is 
38  suggested or recommended, but not required. 
39   
40   
41  II.  DRUG DEVELOPMENT PROGRAM CONSIDERATIONS 
42   
43  A.  Regulatory Considerations 
44   
45  Sponsors developing drugs for mpox should consider the following: 
46   
47    We recommend that sponsors seeking initial advice for mpox drug development submit a 
48  pre-investigational new drug application (pre-IND) meeting request. A pre-IND meeting 
49  allows for early discussion between the sponsor and FDA that can lead to more rapid 
50  review of a subsequent IND submission and facilitate faster clinical trial initiation.  
51   
52    Sponsors should review the draft guidance for industry Formal Meetings Between the 
53  FDA and Sponsors or Applicants of PDUFA Products (December 2017)4 and Division of 
54  Antivirals (DAV) Pre-IND Letter of Instruction, located on the FDA website.5  The pre-
55  IND meeting package should also include the relevant content described in this guidance 
56  (see sections II. B, C, and D). 
57   
58    Sponsors developing drugs for mpox have two options for submitting their pre-IND 
59  meeting requests: 
60   
61   Option 1 (preferred method): Electronic Submissions Gateway (ESG)6  ESG is 
62  an FDA-wide mechanism for accepting electronic IND, new drug application (NDA), 
63  abbreviated new drug application (ANDA), or biologics license application (BLA) 
64  regulatory submissions. The FDA ESG enables the secure submission of premarket 
65  and postmarket regulatory information for review. 
66   
67   Option 2: NextGen Portal7  The Center for Drug Evaluation and Research 
68  (CDER) NextGen Portal is a website providing a limited option for submission of 
69  pre-IND meeting requests and other submissions not subject to the electronic 
70  common technical document (eCTD) requirements.8  
 
4 The final, this guidance will represent FDAs current thinking on this topic.  For most recent version of a guidance, 
check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents 
 
5 See https://www.fda.gov/drugs/pre-ind-consultation-program/division-anti-viral-dav-pre-ind-letter-instruction. 
 
6 See FDAs ESG web page, available at https://www.fda.gov/industry/electronic-submissions-gateway.  
 
7 See CDER NextGen Portal web page, available at http://edm.fda.gov. 
 
8 For further information, see the guidance for industry Providing Regulatory Submissions in Electronic Format  
Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications 
(February 2020). 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
71   
72  B.  Pharmacology/Toxicology Considerations 
73   
74  Sponsors developing drugs for mpox should consider the following: 
75   
76    To support clinical trial initiation for small molecule drugs,9 sponsors should provide the 
77  following data:   
78   
79   Data from good laboratory practice (GLP) compliant10 general toxicology studies in 
80  two species (at least one nonrodent)11 
81   
82   An assessment of standard safety pharmacology parameters (e.g., cardiovascular, 
83  respiratory, and central nervous system assessments), which may be incorporated into 
84  general toxicology studies 
85   
86   The standard battery of genetic toxicology data12 
87   
88    To support clinical trial initiation for biological products,13 sponsors should provide the 
89  following data: 
90   
91   GLP-compliant general toxicology study or studies, when warranted 
92   
93   An assessment of standard safety pharmacology parameters (e.g., cardiovascular, 
94  respiratory, and central nervous system assessments) when warranted, which may be 
95  incorporated into general toxicology studies  
96   
97   Tissue cross-reactivity assay in human tissues, when indicated and technically 
98  feasible  
99   
100    The active pharmaceutical ingredient should be the same between the toxicology studies 
101  and that proposed for use in clinical investigations when evaluating small molecule 
 
9 See the International Council for Harmonisation (ICH) guidance for industry M3(R2) Nonclinical Safety Studies 
for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (January 2010). 
 
10 See 21 CFR part 58, Good Laboratory Practice for Nonclinical Laboratory Studies. 
 
11 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible. The FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible. The FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
 
12 See the ICH guidance for industry S2 (R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals 
Intended for Human Use (June 2012). 
 
13 See the ICH guidance for industry S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived 
Pharmaceuticals (May 2012). 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
102  drugs. Similarly, the biological drug product used in the definitive pharmacology and 
103  toxicology studies and clinical investigations should be comparable. 
104   
105    Additional nonclinical safety studies to support clinical trial initiation may be needed on a 
106  case-by-case basis. Nonclinical safety studies needed to support clinical development of 
107  small molecule drugs and biological products beyond clinical trial initiation are outside 
108  the scope of this guidance. 
109   
110  C.  Virology Considerations 
111   
112  Sponsors developing drugs for mpox should consider the following: 
113   
114    To support clinical trial initiation for small molecule drugs or biological products, 
115  sponsors should provide the following nonclinical virology information: 
116   
117   The hypothesized or determined mechanism of action of the drug, including a 
118  description of the target protein and information supporting the mechanism of action, 
119  such as binding data (e.g., KD values (quantitative measurement of antibody 
120  affinity)), enzymatic inhibition data (IC  and IC  values (50 percent and 90 percent 
50 90
121  inhibitory concentrations)), resistance characteristics, and structural analyses 
122   
123   Cell culture antiviral activity data (EC  and EC  values (50 percent and 90 percent 
50 90
124  effective concentrations) and concentration/response curves) against the current 
125  monkeypox virus outbreak strain/lineage 
126   
127   Data addressing the impact of serum proteins on antiviral activity in cell culture  
128   
129   Cytotoxicity (CC  value (50 percent cytotoxic concentration)) assessments against 
50
130  cells used to characterize antiviral activity, and determination of a selectivity index 
131  (CC  value/EC  value) 
50 50
132   
133   Source and complete amino acid sequence of monoclonal antibodies, including a 
134  description of any Fc (fragment crystallizable) modifications and their expected 
135  pharmacologic effects 
136   
137   Competitive binding analyses for combinations of monoclonal antibodies 
138   
139    Additional nonclinical virology studies that sponsors should conduct either before clinical 
140  trials or during clinical development to support NDA, or BLA submissions for small 
141  molecule drugs or biological products include the following: 
142   
143   Assessments of antiviral activity against geographically and temporally distinct 
144  monkeypox virus isolates 
145   
146   Mitochondrial toxicity and bone marrow precursor cell toxicity assessments for small 
147  molecule inhibitors potentially associated with this risk (e.g., nucleoside analogues) 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
148   
149   Identification of the epitope of monoclonal antibodies and characterization of the 
150  impact of polymorphisms in the target protein contact and the adjacent (within 5 
151  angstroms) amino acid residues on monoclonal antibody susceptibility 
152   
153   Selection and characterization of virus that is resistant to the drug, including 
154  genotypic and phenotypic analyses of polymorphisms occurring at or near resistance-
155  associated positions 
156   
157   Assessments of combination antiviral activity if the drug is anticipated to be used in 
158  combination with other antiviral treatments 
159   
160    The need for studies in animal models of infection will be determined on a case-by-case 
161  basis and should be discussed with FDA. 
162   
163    Sponsors should address the possibility of drug and mpox vaccine interactions for drugs 
164  that may interfere with vaccine effectiveness (e.g., monoclonal antibodies targeting a 
165  critical vaccine antigen). 
166   
167    Clinical trial protocols should include the following information related to planned 
168  virology assessments. The specific types of assays and analysis plans may vary 
169  depending on the objectives of the trial and mechanism of action of the drug. 
170   
171   Description of diagnostic virology assays used for screening and enrollment, 
172  including their regulatory status (e.g., FDA approved, FDA cleared, FDA authorized 
173  (including under emergency use authorization provisions),14 510(k) exempt).  
174   
175   Assay(s) and analysis plans to characterize the impact of drugs on viral DNA levels in 
176  blood, lesion samples, and respiratory samples.  
177   
178   Plans for detection in cell culture of infectious virus from clinical specimens. 
179   
180   Plans to characterize the impact of drugs on antiviral immune responses. 
181   
182   Genotypic and phenotypic resistance analysis plans, including analyses of baseline 
183  viral polymorphisms and treatment-emergent resistance. 
184   
185    FDA performs independent assessments of virologic and resistance data from clinical 
186  trials. Sponsors should consult with FDA before submitting virology datasets to obtain 
187  information on the most recent recommended formats. In the case of next-generation 
188  sequence analysis, sponsors should refer to the technical specifications document 
 
14 See the guidance for laboratories, commercial manufacturers, and FDA staff Policy for Monkeypox Tests to 
Address the Public Health Emergency (September 2022).   
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
189  Submitting Next Generation Sequencing Data to the Division of Antiviral Products (July 
190  2019).15 
191   
192    Sponsors should submit information on sample collection, assays performed, assay 
193  performance characteristics, and other validation approaches for virology assays. Using a 
194  specific procedure, method, or test system in an investigational protocol for a nonclinical 
195  laboratory study, or as a laboratory procedure supporting a clinical trial, does not 
196  constitute FDA endorsement of that procedure, method, or test system, or FDA approval 
197  for clinical laboratory use. 
198   
199    Sponsors should refer to the guidance for industry Antiviral Product Development  
200  Conducting and Submitting Virology Studies to the Agency (June 2006). 
201   
202    Laboratory work with certain orthopoxviruses must comply with applicable regulations16 
203  and should incorporate relevant biosafety and biosecurity procedures as appropriate to the 
204  viruses studied. Sponsors should contact relevant government agencies, such as the 
205  Centers for Disease Control and Prevention and the National Institutes of Health, for 
206  more information regarding biosafety procedures.17 
207   
208  D.  Clinical Considerations 
209   
210  Sponsors developing drugs for mpox should consider the following: 
211   
212    Drugs should undergo sufficient early clinical development, including clinical evaluation 
213  for safety and tolerability, before sponsors submit proposals for evaluation in phase 2 or 
214  phase 3 clinical trials.  
215   
216    To demonstrate substantial evidence of effectiveness,18 development programs should 
217  include randomized controlled clinical trial data in participants with mpox. The primary 
218  endpoint for phase 2 or phase 3 clinical trials should be clinically meaningful and should 
219  demonstrate the clinical benefit with a favorable effect on a meaningful aspect of how a 
220  participant with mpox feels, functions, or survives. Sponsors should discuss appropriate 
221  endpoints for phase 2 and phase 3 clinical trials with the Agency. 
222   
 
15 For the latest version of a technical specifications document, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
16 42 CFR part 73.  Additional information on the Federal Select Agent Program can be found at 
https://www.selectagents.gov.  
 
17 Information on biosafety can be found in the Centers for Disease Control and Prevention and National Institutes 
of Healths (NIHs) Biosafety in Microbiological and Biomedical Laboratories document available at 
https://www.cdc.gov/biosafety/publications/bmbl5/index.htm.  
 
18 See section 505(d) of the FD&C Act and 21 CFR 314.126. Also see the draft guidance for industry Demonstrating 
Substantial Evidence of Effectiveness for Human Drug and Biological Products (December 2019). When final, this 
guidance will represent the FDAs current thinking on this topic.  
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
223    Current data indicate that mpox disproportionately affects racial and ethnic minorities, 
224  who should be represented in clinical trials.19 Sponsors should ensure that clinical trial 
225  sites include geographic locations with a higher concentration of racial and ethnic 
226  minorities to recruit a diverse study population.20 
227   
228    Current data suggest that, in the United States, approximately 40 percent of mpox cases 
229  have occurred in individuals living with human immunodeficiency virus (HIV) 
230  infection.21 Individuals living with HIV infection should not be excluded from clinical 
231  trials. 
232   
233    It may be appropriate to incorporate proposals for adaptive designs in clinical trials 
234  evaluating drugs for mpox.22 Such designs may give more flexibility and allow for 
235  prospectively planned modifications to the design based on its scientific context and 
236  accumulating data from participants in the trial. Sponsors should discuss these plans early 
237  with the Agency, especially when sponsors propose complex innovative designs, 
238  including complex adaptive designs.23 
 
19 Kava CM, Rohraff DM, Wallace B, et al., 2022, Epidemiologic Features of the Monkeypox Outbreak and the 
Public Health Response  United States, May 17October 6, 2022, MMWR Morb Mortal Wkly Rep, 71(45):1449
1456.  
 
20 See the guidance for industry Enhancing the Diversity of Clinical Trial Populations  Eligibility Criteria, 
Enrollment Practices, and Trial Designs (November 2020). 
 
21 See the Centers for Disease Control and Preventions Mpox and HIV web page available at 
https://www.cdc.gov/poxvirus/monkeypox/prevention/hiv.html. 
 
22 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics (November 2019).   
 
23 See the guidance for industry Interacting with the FDA on Complex Innovative Trial Designs for Drugs and 
Biological Products (December 2020). 
  7