Development of Monoclonal Antibody 
Products Targeting SARS-CoV-2 for 
Emergency Use Authorization 
Guidance for Industry 
 
 
 
This guidance is for immediate implementation.
 
 
 
FDA is issuing this guidance for immediate implementation in accordance with 21 CFR 
10.115(g)(2).  Submit one set of either electronic or written comments on this guidance at any 
time.  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.  You should identify all comments with the docket number 
listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this document, contact (CDER) Maria Clary, 240-402-8615. 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2023 
Clinical/Medical
   
Development of Monoclonal Antibody 
Products Targeting SARS-CoV-2 for 
Emergency Use Authorization 
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) 
 
December 2023 
Clinical/Medical  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
I.  INTRODUCTION ............................................................................................................. 1 
II.  BACKGROUND ................................................................................................................ 3 
III.  DISCUSSION ..................................................................................................................... 4 
A.  Criteria for the Issuance of an EUA ............................................................................................. 4 
B.  Guiding Principles ......................................................................................................................... 4 
C.  Development Program Considerations to Support Use Under an EUA ................................... 5 
1. Chemistry, Manufacturing, and Controls ........................................................................................ 5 
2. Pharmacology/Toxicology ............................................................................................................... 8 
3. Virology ........................................................................................................................................... 9 
4. Clinical .......................................................................................................................................... 11 
  Contains Nonbinding Recommendations 
 
Development of Monoclonal Antibody Products Targeting 
SARS-CoV-2 for Emergency Use Authorization 
Guidance for Industry1 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can 
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To 
discuss an alternative approach, contact the FDA staff or office responsible for this guidance as listed on 
the title page.   
 
 
 
 
I.  INTRODUCTION 
 
FDA is issuing this guidance to provide recommendations to sponsors on the development of 
monoclonal antibody (mAb) products targeting SARS-CoV-2 intended for the prevention or 
treatment of COVID-19, including recommendations on addressing the impact of emerging 
variants.  
 
In February 2021, FDA published the guidance for industry Development of Monoclonal 
Antibody Products Targeting SARS-CoV-2, Including Addressing the Impact of Emerging 
Variants, During the COVID-19 Public Health Emergency (February 2021). The guidance was 
published as part of the Agencys efforts to facilitate the development and availability of 
COVID-19 therapeutics for the duration of the COVID-19 public health emergency (PHE), as 
declared under section 319 of the Public Health Service Act (PHS Act). In the Federal Register 
of March 13, 2023 (88 FR 15417), FDA listed certain COVID-19-related guidance documents 
that FDA was revising to continue in effect for 180 days after the expiration of the COVID-19 
PHE declaration on May 11, 2023, during which time FDA planned to further revise the 
guidances. The February 2021 guidance on development of monoclonal antibody products 
targeting SARS-CoV-2 was included in this list. 
 
On February 4, 2020, as amended on March 15, 2023, pursuant to section 564(b)(1)(C) of the 
Federal Food, Drug, and Cosmetic (FD&C) Act, the Secretary of Health and Human Services 
(HHS) has determined that there is a public health emergency, or a significant potential for a 
public health emergency, that affects, or has a significant potential to affect, national security or 
the health and security of United States citizens living abroad, and that the public health 
 
1 This guidance has been prepared by the Office of New Drugs and Office of Pharmaceutical Quality in the Center 
for Drug Evaluation and Research at the Food and Drug Administration. 
 
  1  Contains Nonbinding Recommendations 
 
emergency involves the virus that causes COVID-19.2 On the basis of such determination, the 
Secretary of HHS has declared that circumstances exist justifying the authorization of emergency 
use of drugs and biological products during the COVID-19 pandemic, pursuant to section 564 of 
the FD&C Act, subject to terms of any authorization issued under that section.3 The HHS 
Secretary declaration authorizing FDA to issue emergency use authorizations (EUAs) is distinct 
from, and is not dependent on, an HHS public health emergency declaration under section 319 of 
the PHS Act. Although the PHE declaration under section 319 of the PHS Act has expired, the 
relevant EUA declaration under section 564 of the FD&C Act remains in effect.  
 
Although circumstances have improved, SARS-CoV-2 remains in broad circulation throughout 
the United States. The virus has and continues to evolve over time, and in certain instances, 
mutations in the virus have greatly reduced the activity of monoclonal antibody therapies 
available for the prevention or treatment of COVID-19, resulting in vulnerable populations 
having limited preventative and treatment options. FDA is publishing this guidance to provide its 
current recommendations on the data and information that may be used to support a request for 
an EUA under section 564 of the FD&C Act (21 U.S.C. 360bbb-3) for a mAb product for the 
prevention or treatment of COVID-19. This guidance is intended to remain in effect only for the 
duration of the declaration by the Secretary of HHS under section 564 of the FD&C Act effective 
March 27, 2020, that circumstances exist justifying the authorization of emergency use of drugs 
and biological products during the COVID-19 pandemic (85 FR 18250).4  
 
This guidance does not address the information and data necessary to support the licensure of 
mAb products under section 351 of the Public Health Service Act (42 U.S.C. 262).  
 
Given the need to ensure that sponsors are aware of our current recommendations to facilitate 
timely development of monoclonal antibody products targeting SARS-CoV-2, FDA is issuing 
this guidance for immediate implementation without initially seeking prior comment because the 
Agency has determined that prior public participation is not feasible or appropriate (see 21 CFR 
10.115(g)(2) and section 701(h)(1)(C)(i) of the FD&C Act (21 U.S.C. 371(h)(1)(C)(i))). This 
guidance document is being implemented immediately, but it remains subject to comment in 
accordance with the Agencys good guidance practices. (see 21 CFR 10.115(g)(3)). 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
 
2 U.S. Department of Health and Human Services, Determination of a Public Health Emergency and Declaration 
that Circumstances Exist Justifying Authorizations Pursuant to Section 564(b) of the Federal Food, Drug, and 
Cosmetic Act, 21 U.S.C. 360bbb-3. February 4, 2020; (see 85 FR 7316 (Feb. 7, 2020)). U.S. Department of Health 
and Human Services, Amended Determination of a Public Health Emergency or Significant Potential for a Public 
Health Emergency Pursuant to Section 564(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 360bbb-
3(b). March 15, 2023; (see 88 FR 16644 (March 20, 2023) (Amended Determination). 
 
3 85 FR 18250 (April 1, 2020). This Emergency Use Authorization declaration was effective March 27, 2020. 
 
4 For more information about the determination and declaration under section 564 currently in effect, see COVID-19 
Emergency Use Authorization Declaration (88 FR 16644 (March 20, 2023)). 
 
  2  Contains Nonbinding Recommendations 
 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
II.  BACKGROUND 
 
In 2019, an outbreak of respiratory disease caused by a novel coronavirus began. The virus was 
named SARS-CoV-2, and the disease it causes was named Coronavirus Disease 2019 
(COVID-19). Patients with symptomatic SARS-CoV-2 infection, or COVID-19, can experience 
a wide range of clinical manifestations, with disease severity ranging from mild to 
critical illness.5 
 
The understanding of COVID-19 and its impact on public health has greatly increased since 
COVID-19 was first identified. Notably, during this time, FDA has authorized6 or approved a 
number of drugs and biologics for the prevention or treatment of COVID-19. However, SARS-
CoV-2 has and continues to evolve, resulting in the emergence of multiple variants. A viral 
variant of SARS-CoV-2 has one or more mutations that differentiate it from the original Wuhan 
isolate (Wuhan-Hu1) or the predominant virus variant(s) already circulating in the general 
population. Variants of SARS-CoV-2 are identified by genomic sequences that contain 
mutation(s) in the RNA genome, which could result in amino acid substitutions, insertions, 
and/or deletions in viral proteins. Mutations in genomic regions encoding for viral proteins have 
been shown to negatively impact the expected therapeutic benefit of certain authorized drug 
products, particularly mAb products that bind to specific epitopes7 on the receptor binding 
domain of the SARS-CoV-2 spike protein.  
 
Given this clinical context, FDA will continue to leverage its emergency authorities under 
section 564 of the FD&C Act, when appropriate. FDA may, in its discretion, prioritize requests 
for a mAb product containing sufficient scientific information to assess the known and potential 
benefits and risks of the product when there is no adequate, approved, and available alternative 
as such a product may address an unmet public health need. 
 
It is FDAs expectation that, following submission of an EUA request and issuance of an EUA, a 
sponsor would continue to collect data in any ongoing trials and would also work toward 
submission of a biologics license application as soon as possible.8 
 
 
5 The different severities of COVID-19 illness are described in the National Institutes of Health (NIH) COVID-19 
Treatment Guidelines at https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/. 
 
6 More information about the availability of COVID-19 therapeutics under an EUA can be found at FDAs 
Emergency Use Authorization web page, available at https://www.fda.gov/emergency-preparedness-and-
response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization. 
 
7 For the purposes of this guidance, the term epitope refers to the part of an antigen, in this case the viral protein, to 
which an antibody binds. 
 
8 FDA is required to periodically review the circumstances and appropriateness of an EUA, including the progress 
made toward licensure of a product. See section 564(g)(1) of the FD&C Act (21 U.S.C. 360bbb-3(g)(1)). 
 
  3  Contains Nonbinding Recommendations 
 
 
III.  DISCUSSION 
 
A.  Criteria for the Issuance of an EUA 
 
  On February 4, 2020, as amended on March 15, 2023, pursuant to section 564(b)(1)(C) of 
the FD&C Act, the Secretary of HHS has determined that there is a public health 
emergency, or a significant potential for a public health emergency, that affects, or has a 
significant potential to affect, national security or the health and security of United States 
citizens living abroad, and that the public health emergency involves the virus that causes 
COVID-19.9 On the basis of such determination, the Secretary of HHS has declared that 
circumstances exist justifying the authorization of emergency use of drugs and biological 
products during the COVID-19 pandemic, pursuant to section 564 of the FD&C Act, 
subject to terms of any authorization issued under that section.10 
 
  Based on the above, FDA may issue an EUA for a drug or biological product after FDA 
has determined that the following statutory requirements are met (section 564(c) of the 
FD&C Act): 
 
  Based on the totality of scientific evidence available, including data from adequate 

and well-controlled trials, if available, it is reasonable to believe that: 
 
  The product may be effective to diagnose, prevent, or treat such serious or life-
threatening disease or condition that can be caused by SARS-CoV-2. 
 
  The known and potential benefits of the product, when used to diagnose, prevent, 
or treat the identified serious or life-threatening disease or condition, outweigh the 
known and potential risks of the product.   
 
  There is no adequate, approved, and available alternative to the product for 

diagnosing, preventing, or treating the disease or condition.11 
 
B.  Guiding Principles 
 
Sponsors of mAb products targeting SARS-CoV-2 should consider the following guiding 
principles:  
 
 
9 See footnote 2. 
 
10 See footnote 3. 
 
11 For example, a potential alternative product may be considered unavailable if there are insufficient supplies of 
the approved alternative to fully meet the emergency need. See section III., B., 1., d., of the guidance for industry 
Emergency Use Authorization of Medical Products and Related Authorities (January 2017). 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. 
 
  4  Contains Nonbinding Recommendations 
 
  When scientifically supported, FDA will exercise flexibility regarding the data necessary 
to support the development of mAb products targeting SARS-CoV-2 and expedite the 
review of these data. 
 
  An EUA is not a long-term alternative to obtaining licensure of a mAb product; therefore, 
sponsors should design their development programs with the goal of providing adequate 
data to ultimately support licensure of their products under section 351 of the Public 
Health Service Act.12 
 
  In reviewing requests for EUA, FDAs approach will depend on, among other things, its 
current assessment of a mAb products potential benefit and risk for the intended use and 
population and its expected coverage of important emerging variants.  
 
  Given the rapid rate of SARS-CoV-2 viral evolution demonstrated and the relative 
vulnerability of some mAbs (e.g., mAbs targeting the receptor-binding domain (RBD)) to 
changing variants, FDA encourages the development of mAbs targeting highly conserved 
epitopes that have been relatively preserved over the course of the pandemic.   
 
  FDA strongly recommends that individual mAb products (especially RBD-targeting 
mAbs) be developed with the expectation that they will be combined with one or more 
mAb products that bind to different epitopes to minimize the risk of losing activity 
against emergent variants. FDA encourages collaborations between sponsors of 
individual mAb products to achieve this end. 
 
  Sharing of information regarding SARS-CoV-2 variants among sponsors, consortia, or 
other partnerships may help expedite the development of therapeutics to address these 
variants.  
 
C.  Development Program Considerations to Support Use Under an EUA 
 
1.  Chemistry, Manufacturing, and Controls 
 
Sponsors of mAb products targeting SARS-CoV-2 should consider the following chemistry, 
manufacturing, and controls recommendations: 
 
  When feasible and scientifically supported, sponsors should attempt to leverage 
experience obtained from other mAb products in development and already licensed mAb 
therapies. Specific examples include the following: 
 
  The use of existing manufacturing platforms to establish a manufacturing process for 

investigational product development. 
 
 
12 FDA is required to periodically review the circumstances and appropriateness of an EUA, including the progress 
made toward licensure of a product. See section 564(g)(1) of the FD&C Act (21 USC 360bbb-3(g)(1)). 
 
  5  Contains Nonbinding Recommendations 
 
  The selection of manufacturing facilities13 that have experience in manufacturing 

biotechnology products and have an established inspectional history, including 
acceptable outcomes from recent inspection(s) (including using information shared by 
trusted foreign regulatory partners through mutual recognition agreements14).15  
 
  The potential to use already obtained modular data for viral clearance validation, and 

a purification process validation (e.g., impurity clearance). 
 
  The selection of analytical methods that have already been qualified or validated. The 

potency assay for a new mAb targeting SARS-CoV-2 spike protein should use the 
predominant circulating variant at that time. The potency assay16 formats (including 
binding assays and/or neutralizing assays) for a previous mAb may be adapted for the 
new mAb and should use revised reagents that evaluate the new variant protein(s) or 
pseudotyped virus/virus-like particles in the assay(s). Once a potency assay is 
established for release and stability testing of a specific anti-SARS-CoV-2 mAb, the 
assay does not need to be requalified or revalidated for use with new variants because 
the purpose of the assay is to ensure lot-to-lot consistency. However, the sponsor is 
expected to assess the mAb against newly arising variants to ensure that the product 
remains effective (see Virology section). 
 
  The use of data that may be available from public consortia or partnerships that may 

contribute to understanding product performance. 
 
  The leveraging of related product quality data (e.g., formulation development) to 

support in-use stability and compatibility. 
 
  The use of prior development experience to anticipate the best dosage form, route of 

administration, and formulation (composition) selection.  
 
  Sponsors that may not be able to leverage experience obtained from other mAb products 
in development or already licensed are also encouraged to develop mAbs against new 
SARS-CoV-2 variants. Specific options include the following: 
 
  Exploring opportunities for less experienced manufacturers to partner with more 

experienced manufacturers to leverage all available development tools 
 
13 For information on facility recommendations pertaining to EUAs, see section III., D., 2., a., bullet 6 and section 
III., E., 5., a., of the guidance for industry and other stakeholders Emergency Use Authorization of Medical Products 
and Related Authorities. 
 
14 See FDAs Mutual Recognition Agreement web page, available at https://www.fda.gov/international-
programs/international-arrangements/mutual-recognition-agreement-mra. 
 
15 See 21 CFR 601.20. 
 
16 See the draft guidance for industry Potency Assay Considerations for Monoclonal Antibodies and Other 
Therapeutic Proteins Targeting Viral Pathogens (March 2023). 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  Contains Nonbinding Recommendations 
 
 
  Exploring opportunities to partner with experienced manufacturers to use 

manufacturing facilities with inspection histories and mAb manufacturing experience 
 
  Using publicly available prior knowledge related to upstream and downstream 

manufacturing processes for mAbs 
 
  Using well-established cell substrates 

 
  FDA strongly recommends that sponsors discuss with FDA in advance (well before they 
occur) time-critical elements of the development program. Specific examples include the 
following:   
 
  A plan that describes key aspects of the manufacturing development, including plans 

for scale-up, particularly if plans include use of facilities that do not have recent 
acceptable inspection history or experience manufacturing mAbs. 
 
  Comparability protocols that include a detailed description of tests and acceptance 

criteria to evaluate the impact of manufacturing process changes on product quality. 
 
  Plans to address shortages of raw materials for manufacturing or supplies for infusion 

of the mAb.   
 
  A strategy for establishing a shelf life for the intended mAb product targeting SARS-

CoV-2. This may include opportunities to leverage related product data to justify the 
proposed shelf life. 
 
  Plans to meet predicted product demand. 

 
  Certain approaches may be appropriate for limited early-phase development to enable 
rapid introduction of the product into clinical trials. Specific examples include the 
following:  
 
  Use of a stable cell pool in lieu of a clonally derived cell bank to generate early 

clinical batches. Risks of this approach include the ability to ensure comparability to 
products manufactured with a clonally derived cell bank. In addition, the upstream 
manufacturing process may require the use of antibiotics as selection reagents for 
more passages than would be needed when manufacturing using a clonally derived 
cell bank; therefore, clearance of antibiotics should be demonstrated and an 
evaluation of the permissible daily exposure should be provided. 
 
  Consideration of interim results from limited safety testing results (e.g., for cell 

banks, unprocessed bulk harvest) to begin first-in-human clinical trial(s) with full 
study reports to be available at time negotiated with FDA and submitted to the 
investigational new drug application (IND); however, when other therapies become 
available under EUA or through marketing approval, this limited safety testing may 
  7  Contains Nonbinding Recommendations 
 
no longer be appropriate. Sponsors are encouraged to discuss the IND safety testing 
package in a pre-IND meeting with the review team.  
 
  Flexibility in the amount of stability study results provided in the IND submission to 

support the initiation of first-in-human clinical trials. 
 
  Use of two robust orthogonal virus clearance steps when modular/generic virus 

clearance data are not available.  
 
  FDA may decide not to require completed process validation (excluding validation of the 
sterilization and aseptic processes for drug product) to support an EUA. However, 
sufficient process knowledge and/or characterization is expected and should be consistent 
with the overall benefit-risk assessment of the product. If only limited process validation 
data are provided, the sponsor can propose additional elements for the control strategy. 
These elements can include additional controls in the manufacturing processes, taking 
into consideration the criticality assessment for individual process parameters, the ranges 
proposed for a given parameter, or the inclusion of additional in-process measurements or 
release specifications. 
 
2.  Pharmacology/Toxicology 
 
Sponsors of mAb products targeting SARS-CoV-2 should consider the following 
pharmacology/toxicology recommendations: 
 
  The Agency intends to be flexible regarding nonclinical safety data expectations (e.g., 
content and/or timing of data submission to the IND) for mAb products targeting SARS-
CoV-2 to support clinical trial initiation. The degree of flexibility warranted will be 
influenced by the risk characteristics of the product (e.g., original source and isotype of 
the mAb, nature of any amino acid changes/Fc domain modifications, manufacturing 
processes, product quality attributes), route of administration, potential coverage of 
important emerging variants, and a benefit-risk assessment for the intended trial 
population (e.g., hospitalized, nonhospitalized, healthy trial subjects). Thus, FDA 
strongly recommends that sponsors discuss the nonclinical safety data needed to support 
product administration in a specific clinical trial with the Agency through the pre-IND 
consultation process.  
 
  Depending on the specific FDA recommendations provided during the pre-IND 
consultation process, the nonclinical safety assessment for mAb products targeting 
SARS-CoV-2 would typically follow approaches outlined in the ICH guidance for 
industry S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals 
(May 2012) and include the following: 
 
  8  Contains Nonbinding Recommendations 
 
  A tissue cross-reactivity study using a panel of human tissues.17 When a mAb binds 

to human tissues in the tissue cross-reactivity study, FDA recommends evaluating 
mAb binding to select tissues from nonclinical species to assist in species selection 
for repeat-dose toxicology testing. When binding of potential clinical concern is 
observed (e.g., cell membrane binding), FDA recommends discussing these data with 
the Agency because additional studies may be needed to help inform the potential 
clinical relevance of the findings. 
 
  A short duration (i.e., 3 weeks of treatment) repeat-dose toxicology study in a single 

species, using the clinical formulation and route of administration(s) intended for 
clinical administration, that includes all standard toxicity endpoints, including 
toxicokinetic analysis. FDA also recommends discussing specific study design 
considerations with the Agency. 
 
  Toxicology studies with specific mAb combinations are not needed for mAb products 
targeting SARS-CoV-2 proteins, so mAb products can be evaluated separately in 
toxicology studies. If a sponsor evaluates mAb products in combination, FDA 
recommends using the same ratio intended for clinical administration. 
 
  To support administration of mAb products during pregnancy, FDA recommends 
conducting a tissue cross-reactivity study using relevant human tissues or studies using 
alternative protein interaction technologies, with appropriate justification. If no specific 
concerns are identified in the toxicology studies, developmental and reproductive 
toxicology studies are not needed. 
 
3.  Virology 
 
Sponsors of mAb products targeting SARS-CoV-2 should consider the following virology 
recommendations: 
 
  A broad approach should initially be used to characterize the impact of amino acid 
changes, insertions, or deletions throughout the mAb target protein to identify regions 
where changes specifically impact mAb binding or activity, and subsequent analyses and 
surveillance can focus on these regions. 
 
  Sponsors should characterize the epitopes to which mAb products bind to enable 
identification of polymorphisms, which may affect binding, and to inform decisions 
regarding mAb products planned for use in a combination therapy. 
 
  Sponsors should monitor SARS-CoV-2 genomic databases continually for emerging 
SARS-CoV-2 variants and should evaluate phenotypically any specific variants that are 
prevalent or becoming prevalent that harbor substitutions in or near (<5 A) the target 
 
17 See the guidance for industry Points to Consider in the Manufacture and Testing of 
Monoclonal Antibody Products for Human Use (February 1997).  
 
  9  Contains Nonbinding Recommendations 
 
epitope. Sponsors should conduct a more thorough analysis to include other substitutions 
at the same amino acid positions.   
 
  Sponsors should characterize mAb products with respect to epitope binding (affinity 
equilibrium dissociation constant (K ) and noncompetitive binding for combinations). 
D
Sponsors should characterize the mechanism of action for SARS-CoV-2 neutralization 
(e.g., blocking spike protein/receptor binding domain interaction with ACE2). 
 
  Sponsors should determine the neutralizing activity (half maximal effective concentration 
(EC ) value) of investigational mAb products, individually and if applicable in 
50
combination, against an array of circulating variants representing the diversity of the 
target protein and epitope to which the mAb binds. 
 
  Sponsors should assess for the potential of antibody dependent enhancement (ADE). Cell 
culture ADE studies should assess for enhancement at concentrations that range from 
125-fold below the EC  value to 10-fold above the EC  value of the mAb. 
50 50
 
  Sponsors should characterize the Fc-mediated antibody effector functions of 
investigational mAb products, individually if part of a combination, using Fc receptor 
binding assays and in cell culture systems with appropriate effector molecule readouts. 
 
  Sponsors should evaluate the neutralizing activity of mAbs, individually and if applicable 
in combination, against SARS-CoV-2 variants or pseudotyped virus-like particles 
harboring substitutions known to confer reduced susceptibility to other authorized or 
approved antibody products targeting SARS-CoV-2 infectivity. Activity against 
pseudotyped virus-like particles is useful for expediency with respect to arising variants, 
but ultimately activity against authentic viruses should be determined. 
 
  SARS-CoV-2 or recombinant vesicular stomatitis virus expressing spike protein should 
be serially passaged in cell culture in the presence of the mAb product, individually and if 
applicable in combination, to select for resistant variants to understand the potential risk 
and nature of treatment-emergent resistance. Sponsors should characterize genotypically 
and phenotypically the variants selected in this manner.  
 
  Sponsors should assess the potential for cross-resistance between novel mAb products 
and approved or authorized mAb products, for example, by assessing the effect of 
resistance-associated substitutions for a novel mAb on the activity of approved or 
authorized mAbs in cell culture studies using recombinant viruses or virus-like particles.  
 
  Clinical protocols should include detailed plans to (1) characterize the impact of SARS-
CoV-2 genetic variability on clinical and virologic outcomes (i.e., baseline resistance 
analyses) and (2) identify SARS-CoV-2 genetic changes associated with treatment (i.e., 
treatment-emergent resistance analyses). 
  10  Contains Nonbinding Recommendations 
 
  Sponsors should consult appropriate biosafety guidelines when conducting virology 
studies.18 
 
  Sponsors should also reference the guidance for industry COVID-19: Developing Drugs 
and Biological Products for Treatment or Prevention (November 2023) and the guidance 
for industry Antiviral Product Development  Conducting and Submitting Virology 
Studies to the Agency (June 2006).  
 
4.  Clinical 
 
Sponsors of mAb products targeting SARS-CoV-2 should consider the following clinical 
recommendations: 
 
  In general, sponsors should design mAb product development programs evaluating the 
treatment or prevention of COVID-19 to assess the effect of investigational products on 
clinically meaningful aspects of the disease.19  
 
  Sponsors considering the use of a surrogate endpoint (e.g., neutralizing antibody titers) to 
support an EUA in situations where viral variants have affected the efficacy of currently 
authorized or approved therapeutic (treatment or prevention) options should seek early 
input from the Agency on their proposals.   
 
  Sponsors should scientifically justify the selection of doses and regimens for phase 3 
trials and discuss with the Agency. For example, results from a phase 2 dose-finding 
study can directly support the selection of doses and regimens for phase 3 trials.  
 
  The size and composition of the safety database needed to support an EUA will depend 
on factors such as the mAb products proposed use, the proposed patient population, and 
the extent and nature of the prior clinical experience with the product and with related 
products.  
 
  Sponsors should also reference the guidance for industry COVID-19: Developing Drugs 
and Biological Products for Treatment or Prevention for additional recommendations on 
trial populations, trial design, efficacy endpoints, safety, and statistical considerations.  
 
 
18 For biosafety considerations from NIH, see the NIH Guidelines for Research Involving Recombinant or Synthetic 
Nucleic Acid Molecules and the FAQs  Interim Laboratory Biosafety Guidance for Research with SARS-CoV-2 
and IBC Requirements under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules, available at https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.pdf. See also the Centers for 
Disease Control and Preventions and the National Institutes of Healths guideline Biosafety in Microbiological and 
Biomedical Laboratories, available at https://www.cdc.gov/labs/BMBL.html. Studies should also follow applicable 
federal policies and guidelines related to dual use research of concern, available at 
https://www.phe.gov/s3/dualuse/Pages/default.aspx. 
 
19 See the guidance for industry COVID-19: Developing Drugs and Biological Products for Treatment or 
Prevention. 
  11