COVID-19: Developing 
Drugs and Biological 
Products for Treatment or 
Prevention 
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, 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) 
 
November 2023 
Clinical/Medical 
   
COVID-19: Developing 
Drugs and Biological 
Products for Treatment or 
Prevention 
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 
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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) 
 
November 2023 
Clinical/Medical 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DISCUSSION .................................................................................................................... 2 
A.  Treatment Trials ............................................................................................................................ 2 
1. Population ........................................................................................................................................ 2 
2. Trial Design and Conduct ................................................................................................................ 5 
3. Efficacy Endpoints ........................................................................................................................... 8 
4. Safety Considerations .................................................................................................................... 10 
5. Statistical Considerations .............................................................................................................. 11 
B.  Prevention Trials .......................................................................................................................... 12 
APPENDIX A .............................................................................................................................. 14 
APPENDIX B .............................................................................................................................. 16 
APPENDIX C .............................................................................................................................. 18 
  Contains Nonbinding Recommendations 
1  COVID-19: Developing Drugs and Biological Products for 
2  Treatment or Prevention 
3  Guidance for Industry1 
4   
5   
6   
7  This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
8  this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
9  can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
10  To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
11  title page 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  The purpose of this guidance is to assist sponsors in the clinical development of drugs2 for the 
18  treatment or prevention of COVID-19. This guidance describes FDAs current recommendations 
19  for phase 2 and phase 3 trials with a focus on trial population, trial design, efficacy endpoints, 
20  safety considerations, and statistical considerations. There may be additional considerations for 
21  some biological products (e.g., cellular and gene therapies and blood products), so FDA 
22  encourages sponsors to reach out to the applicable review division as appropriate.  
23   
24  The development of drugs for the treatment of Long COVID-19, preventative vaccines3 and 
25  convalescent plasma4 is not within the scope of this guidance. 
26   
27  FDA is implementing this guidance without prior public comment because the Agency has 
28  determined that prior public participation is not feasible or appropriate (see 21 CFR 10.115(g)(2) 
 
1 This guidance has been prepared by the Office of New Drugs and the Office of Biostatistics in the Center for Drug 
Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and 
Drug Administration. 
 
2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified. 
 
3 Clinical trials of preventative vaccines raise different and additional considerations, including those pertaining to 
subject selection, safety monitoring, and effectiveness evaluation. We encourage developers of preventative 
vaccines to contact the Office of Vaccines Research and Review in CBER and to see the guidance for industry 
Development and Licensure of Vaccines to Prevent COVID-19 (October 2023). 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 FDA has issued guidance to provide recommendations to health care providers and investigators on the 
administration and study of investigational convalescent plasma collected from individuals who have recovered 
from COVID-19 (COVID-19 convalescent plasma). See the guidance for industry Investigational COVID-19 
Convalescent Plasma (October 2023). 
 
1  Contains Nonbinding Recommendations 
29  and (g)(3). FDA made this determination because although the COVID-19-related public health 
30  emergency under section 319 has expired, SARS-CoV-2 continues to circulate, COVID-19 
31  remains a serious health risk for some individuals, and there is a need to ensure that sponsors are 
32  aware of FDAs recommendations to facilitate timely development of drugs and biological 
33  products for treatment and prevention of COVID-19. This guidance document is being 
34  implemented immediately, but it remains subject to comment in accordance with the Agencys 
35  good guidance practices. 
36   
37  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
38  Instead, guidances describe the Agencys current thinking on a topic and should be viewed 
39  only as recommendations, unless specific regulatory or statutory requirements are cited. The 
40  use of the word should in Agency guidances means that something is suggested or 
41  recommended, but not required. 
42   
43   
44  II.  BACKGROUND 
45   
46  COVID-19, the disease caused by the SARS-CoV-2 virus, can range from mild to severe or 
47  critical disease, the latter including pneumonia, severe acute respiratory syndrome, multi-organ 
48  failure, and death. Additionally, the SARS-CoV-2 virus can cause asymptomatic infection.5 
49  Clinical management includes the use of preventative vaccines and therapeutic agents (e.g., 
50  direct antivirals, immunomodulators) and supportive care, such as supplemental oxygen, 
51  mechanical ventilation, and extracorporeal membrane oxygenation.6  
52   
53   
54  III.  DISCUSSION 
55   
56  A.  Treatment Trials 
57   
58  1.  Population 
59   
60  Sponsors of drugs to treat COVID-19 should consider the following: 
61   
62    The enrolled population should reflect the intended use of the product. For example:  
63   
64    Non-hospitalized individuals at standard risk of progression to serious disease  
65    Non-hospitalized individuals at high risk of progression to serious disease 
66    Hospitalized individuals requiring supplemental oxygen  
67    Hospitalized individuals with respiratory failure  
68   
 
5 See the Centers for Disease Control and Prevention Interim Clinical Guidance for Management of Patients with 
Confirmed Coronavirus Disease (COVID-19), available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-
guidance-management-patients.html. 
 
6 See the National Institutes of Health (NIH) COVID-19 Treatment Guidelines, available at 
https://www.covid19treatmentguidelines.nih.gov/management/. 
2  Contains Nonbinding Recommendations 
69    For treatment trials, sponsors should document diagnosis of laboratory-confirmed SARS-
70  CoV-2 as well as the duration of symptoms before treatment.  
71   
72    For treatment trials, FDA recommends that sponsors categorize the baseline severity of 
73  COVID-19 in the enrolled population. The criteria used to describe baseline disease 
74  severity should incorporate objective measures. Examples of disease severity criteria are 
75  provided in Appendix A. 
76   
77    Clinical trials intended to demonstrate prevention of serious outcomes, including 
78  hospitalization or death, should include groups of persons at high risk of progression to 
79  severe disease.7 
80   
81    Age is one of the strongest risk factors for severe COVID-19 outcomes. To the fullest 
82  extent possible, older adults, including individuals 75 years of age and older, should be 
83  represented in relevant clinical trials.8 Sponsors should consider conducting trials in 
84  nursing homes or other eldercare facilities. 
85   
86    Individuals from underrepresented racial and ethnic groups should be represented in 
87  clinical trials. Sponsors should select clinical study site locations to facilitate enrollment 
88  of a diverse study population.9 
89   
90    Studies to characterize the effect of extrinsic factors (e.g., drug-drug interactions) and 
91  intrinsic factors (e.g., renal impairment or hepatic impairment) on the pharmacokinetics 
92  of a drug should be conducted early in development to inform the management of drug-
93  drug interactions and inclusion of individuals with renal and/or hepatic impairment in 
94  clinical trials as appropriate. Sponsors should consider recommendations in relevant 
95  guidances for industry.10 
96   
97    The principles outlined in this document can be used to guide drug development for 
98  children and for pregnant and lactating individuals. There is a need to generate clinical 
99  trial data to inform the use of drugs in these populations. 
 
7 See the NIH COVID-19 Treatment Guidelines Overview of COVID-19, available at 
https://www.covid19treatmentguidelines.nih.gov/overview/overview-of-covid-19/. 
 
8 See the guidance for industry Enhancing the Diversity of Clinical Trial Populations  Eligibility Criteria, 
Enrollment Practices, and Trial Designs (November 2020). 
 
9 Ibid. 
 
10 See the guidances for industry In Vitro Drug Interaction Studies  Cytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions (January 2020), Clinical Drug Interaction Studies  Cytochrome P450 Enzyme- and 
Transporter-Mediated Drug Interactions (January 2020), Pharmacokinetics in Patients with Impaired Hepatic 
Function: Study Design, Data Analysis, and Impact on Dosing and Labeling (May 2003), and the draft guidance for 
industry Pharmacokinetics in Patients with Impaired Renal Function  Study Design, Data Analysis, and Impact on 
Dosing and Labeling (September 2020). 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. 
 
3  Contains Nonbinding Recommendations 
100   
101    Because COVID-19 during pregnancy may increase the risk of severe symptoms and 
102  preterm birth, sponsors should ensure that adequate nonclinical studies have been 
103  completed so that pregnant individuals can be enrolled in phase 3 (efficacy) clinical 
104  trials.11 
105   
106    FDA encourages enrolling lactating individuals in phase 3 (efficacy) clinical trials.  
107   
108    Children should not be categorically excluded from clinical trials of investigational 
109  COVID-19 products in which there is a prospect for direct benefit.12 
110   
111    Sponsors are encouraged to discuss pediatric drug development with FDA early in 
112  the course of clinical development, including the potential for extrapolation of 
113  efficacy data from studies in adults, appropriate pharmacokinetic trials in 
114  pediatric subjects to support dose selection, and the recommended size of the 
115  preapproval safety database in children. In addition, disease severity classification 
116  should reflect age-appropriate norms, as applicable. Decisions on the timing of 
117  initiating pediatric studies depend on several factors, including but not limited to 
118  the amount of available clinical and/or nonclinical safety data for the drug. For 
119  example, if dosing recommendations for a drug are the same for adults and 
120  adolescents13 and there is a prospect of direct benefit, then adolescents should be 
121  included in the initial phase 3 clinical trials. 
122   
123    Sponsors are encouraged to submit an initial pediatric study plan as soon as 
124  practicable.14 
125   
126    Under the Pediatric Research Equity Act, all applications for new active 
127  ingredients (which include new salts and new fixed combinations), new 
128  indications, new dosage forms, new dosing regimens, or new routes of 
129  administration are required to contain an assessment of the safety and 
130  effectiveness of the product for the claimed indication or indications in pediatric 
131  populations unless this requirement is waived, deferred, or inapplicable.15 FDA 
132  intends to work with sponsors to reach agreement on the initial pediatric study 
133  plan and any pediatric trial protocols as quickly as possible to avoid any 
 
11 FDA has proposed relevant recommendations in the draft guidance for industry Pregnant Women: Scientific and 
Ethical Considerations for Inclusion in Clinical Trials (April 2018). When final, this guidance will represent the 
FDAs current thinking on this topic. 
 
12 For additional safeguards for children in clinical investigations, see 21 CFR part 50, subpart D. 
 
13 For the purposes of this guidance, adolescents are defined as age 12 to younger than 18 years of age. 
 
14 See 505B(e) of the FD&C Act. Additionally, FDA has proposed relevant recommendations in 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).  
 
15 See 21 U.S.C. 355c. 
 
4  Contains Nonbinding Recommendations 
134  unnecessary delays in the initiation of trials or submission of any marketing 
135  application. 
136   
137  2.  Trial Design and Conduct 
138   
139  Sponsors of drugs to treat COVID-19 should consider the following: 
140   
141    FDA strongly recommends that drugs to treat COVID-19 be evaluated in randomized, 
142  controlled, double-blind clinical trials.  
143   
144    Typically, trials should be designed as placebo-controlled superiority studies. An add-
145  on placebo design (i.e., the investigational agent or placebo added on to standard of 
146  care) may be necessary to maintain equipoise. 
147   
148    For agents with a similar mechanism of action as the background standard of care 
149  (e.g., direct antiviral agent as the investigational agent when the standard of care is 
150  also a direct antiviral agent), an active-comparator controlled study design may be 
151  considered. A superiority trial design or noninferiority design16 may be appropriate.  
152   
153    Sponsors are encouraged to use quantitative clinical pharmacology approaches that 
154  leverage all available information for selection of dosing regimen(s) to be evaluated in 
155  clinical trials.17 
156   
157    Sponsors should plan to collect baseline vaccination status, changes in vaccination status 
158  during the trial, and baseline and concomitant medication use, including COVID-19 
159  standard of care therapies. 
160   
161    Sponsors should address the possibility of drug and COVID-19 vaccine interactions for 
162  drugs that may interfere with vaccine effectiveness (i.e., monoclonal antibodies targeting 
163  the vaccine antigen). Sponsors should consult with the Agency early in the development 
164  program for such drugs.  
165   
166    SARS-CoV-2 has and continues to evolve, resulting in the emergence of SARS-CoV-2 
167  with genetic changes that may impact the effectiveness of antiviral drugs. Sponsors 
168  should determine the antiviral activity (EC  and EC  values) of their drug against 
50 90
169  currently predominant and emerging U.S. variants.  
170   
171    Using an antiviral drug to treat COVID-19 may contribute to the emergence of viruses 
172  with reduced susceptibility to the drug or to other approved or investigational drugs. 
173  Sponsors should characterize drug resistance pathways and the potential for cross-
 
16 The noninferiority margin must be sufficiently supported to conduct a noninferiority trial and the justification 
should be discussed with FDA. See the guidance for industry Non-Inferiority Clinical Trials to Establish 
Effectiveness (November 2016). 
 
17 See the guidances for industry Population Pharmacokinetics (February 2022) and Exposure-Response 
Relationships  Study Design, Data Analysis, and Regulatory Applications (May 2003). 
5  Contains Nonbinding Recommendations 
174  resistance to other drugs using both nonclinical and clinical studies. Details regarding 
175  drug resistance analysis are provided in Appendix B. Sponsors should also refer to the 
176  guidance for industry Antiviral Product Development  Conducting and Submitting 
177  Virology Studies to the Agency (June 2006).  
178   
179    Clinical trial protocols should include plans to characterize the impact of drugs on viral 
180  shedding and immune responses as described in Appendix C. 
181   
182    Decentralized clinical trials (DCTs) may play a role in COVID-19 drug development 
183  programs. Sponsors considering a DCT should plan early discussions with the 
184  appropriate review division, as a DCT may introduce additional complexities related to 
185  feasibility, design, implementation, and analysis of the data.18,19 
186   
187    Sponsors should consider several factors when determining if conducting a DCT is 
188  appropriate, selecting the location of a trial visit, and/or selecting personnel 
189  performing an assessment. These factors include the following: 
190   
191    The severity of COVID-19  
192   
193    The nature of the investigational product (e.g., ease of administration, safety 
194  profile, stability profile, storage conditions)  
195   
196    The type of trial procedure or assessment (e.g., administration of investigational 
197  product, clinical laboratory assessment, clinical outcome assessment, or adverse 
198  event assessment/follow-up)  
199   
200    Sponsors considering the use of adaptive design elements in their clinical trial should 
201  review the guidance for industry Adaptive Designs for Clinical Trials of Drugs and 
202  Biologics (November 2019). If a trial incorporates any adaptations to the sample size, 
203  dosing arms, or other design features, sponsors should prospectively plan the design in a 
204  manner to ensure control of the type I error rate and reliable treatment effect estimation. 
205   
206    FDA strongly discourages disseminating data from ongoing trials. Knowledge of 
207  accumulating data by trial investigators and subjects can adversely affect subject accrual, 
208  adherence, and retention, as well as endpoint assessment, compromising the ability of the 
209  trial to reliably achieve its objective in a timely manner. Issues with trial conduct caused 
210  by knowledge of interim results are difficult to predict and generally impossible to adjust 
211  for in statistical analyses. Therefore, releasing interim results could have ramifications on 
212  the integrity of the ongoing trial and the ability to collect reliable and interpretable data 
 
18 See the draft guidance for industry Decentralized Clinical Trials for Drugs, Biological Products, and Devices 
(May 2023). When final, this guidance will represent the FDAs current thinking on this topic. 
 
19 See the draft guidance for industry, investigators, and other stakeholders Digital Health Technologies for Remote 
Data Acquisition in Clinical Investigations (December 2021). When final, this guidance will represent the FDAs 
current thinking on this topic. 
 
6  Contains Nonbinding Recommendations 
213  needed to support regulatory decision-making. If sponsors intend to conduct interim 
214  analyses, FDA recommends they prospectively plan these analyses and incorporate 
215  processes to maintain the integrity of the trial (e.g., using an independent DMC).20 FDA 
216  recognizes there may be exceptional circumstances in which a sponsor determines it 
217  needs to disseminate results for safety or other reasons. In such situations, the sponsor is 
218  strongly encouraged to discuss with FDA before releasing such results.  
219   
220    FDA encourages sponsors to incorporate prospectively planned criteria to stop the trial 
221  for futility (lack of efficacy) or harm in any confirmatory trial. The stopping criteria 
222  should aim to ensure a high probability of halting the trial if the drug is harmful (e.g., 
223  associated with a higher risk of death), a reasonable probability of halting the trial if the 
224  drug is ineffective, and a high probability of continuing the trial if the drug is effective. 
225   
226    FDA encourages sponsors to use an independent, external data monitoring committee 
227  (DMC) to ensure subject safety and trial integrity. 
228   
229    Sponsors should submit the DMC charter to FDA before enrolling subjects. 
230   
231    Sponsors should ensure there will be appropriate DMC monitoring to safeguard the 
232  welfare of subjects, accounting for important factors such as the expected enrollment 
233  rate, the expected lag time to analyze interim data for DMC meetings, and the 
234  frequency of DMC meetings.21 
235   
236    The trial should aim to minimize missing data. The protocol should distinguish between 
237  discontinuation from the study drug and withdrawal from study assessments. Trial 
238  subjects may choose to discontinue treatment during the trial for various reasons, such as 
239  experiencing adverse events or perceived lack of efficacy. Unless the subject withdraws 
240  consent,22 sponsors should encourage subjects who discontinue therapy to remain in the 
241  study and to continue follow-up for key safety and efficacy assessments. Virtual follow-
242  up is acceptable, if appropriate, and the aim should be to record vital status for all 
243  subjects. 
244   
245    Applicable clinical trials need to be registered at www.ClinicalTrials.gov as required by 
246  42 CFR part 11. FDA encourages responsible parties to promptly update 
247  www.clinicaltrial.gov with the results of completed trials given their public health 
248  importance.  
249   
 
20 See guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics. 
 
21 See the guidance for industry Establishment and Operation of Clinical Trial Data Monitoring Committees (March 
2006).  
 
22 Withdrawal of consent refers to a subjects voluntary termination of participation in the clinical trial during the 
course of the trial. The reason for withdrawal of consent should be captured in a case report form. 
7  Contains Nonbinding Recommendations 
250  3.  Efficacy Endpoints 
251   
252  Sponsors of drugs to treat COVID-19 should consider the following: 
253   
254    The drug development program should evaluate the effect of the investigational drug 
255  relative to placebo or an active comparator on clinically meaningful aspects of the 
256  disease. The relevance and appropriateness of measures may depend on factors such as 
257  the mechanism of action of the drug, the population studied, the clinical setting, the phase 
258  of drug development, and/or baseline disease severity (see Appendix A). 
259   
260    Examples of important clinical outcome measures in treatment trials include the 
261  following: 
262   
263    All-cause mortality. 
264   
265    Respiratory failure (i.e., need for mechanical ventilation, extracorporeal membrane 
266  oxygenation, noninvasive positive pressure ventilation, or high-flow nasal cannula 
267  oxygen delivery). 
268   
269    Need for invasive mechanical ventilation. 
270   
271    Need for hospitalization.  
272   
273    Objective measures of sustained improvement (e.g., return to room air or baseline 
274  oxygen requirement). 
275   
276    Sustained symptom alleviation or resolution. For trials evaluating non-hospitalized 
277  patients, this can be defined as occurring when no key COVID-19-related symptom 
278  scored higher than a prespecified threshold over a clinically meaningful time period 
279  (as documented using a patient-reported outcome instrument).23  
280   
281    Clinical status using an ordinal scale that incorporates multiple clinical outcomes of 
282  interest ordered by their clinical importance.  
283   
284   
285    The choice, time frame, and interpretation of endpoints may differ depending on the 
286  population evaluated in the trial. For example, 
287   
 
23 See the guidances for industry Assessing COVID-19-Related Symptoms in Outpatient Adult and Adolescent 
Subjects in Clinical Trials of Drugs and Biological Products for COVID-19 Prevention or Treatment (September 
2020) and Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims 
(December 2009) for additional information on using patient-reported outcome measures to define clinical recovery. 
Also see FDA Patient-Focused Drug Development Guidance Series which can be found at 
https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-
series-enhancing-incorporation-patients-voice-medical. 
 
8  Contains Nonbinding Recommendations 
288    In a trial in severe and/or critically ill patients, examples of appropriate endpoints 
289  could be   
290   
291    All-cause mortality at an appropriate time point (e.g., at least 28 days for 
292  hospitalized noncritically ill patients,24 60 days for critically ill patients25) 
293   
294    Proportion of patients alive and free of respiratory failure at an appropriate time 
295  point (e.g., at least 28 days for hospitalized noncritically ill patients, 60 days for 
296  critically ill patients) 
297   
298    In an outpatient treatment trial, examples of appropriate endpoints could be 
299   
300    Proportion of patients progressing to hospitalization or death by an appropriate 
301  time point (e.g., at least 28 days). 
302   
303    Time to sustained symptom alleviation or resolution assessed over an appropriate 
304  duration.  
305   
306    For primary endpoints other than all-cause mortality, a treatment effect could be driven 
307  by nonmortality components (e.g., hospitalization) despite increased mortality while on 
308  the investigational drug. Therefore, analyses of all-cause mortality will be important 
309  regardless of the selected primary endpoint. Additionally, powering the trial based on 
310  other endpoints, such as time to sustained recovery, may result in less precision in the 
311  assessment of all-cause mortality attributable to a smaller patient sample size. Depending 
312  on the population and mechanism of action of the investigational drug(s), additional 
313  consideration may be needed to determine if the sample size is sufficient to provide an 
314  adequate assessment of mortality. 
315   
316    In their endpoint definition, sponsors should address the occurrence of relapses to ensure 
317  adequate assessment of the durability of response. 
318   
319    In phase 2 treatment trials, a virologic measure may be acceptable as a primary endpoint 
320  to support progression to a phase 3 clinical endpoint trial. However, virologic endpoints 
321  are not appropriate as primary endpoints in a phase 3 trial because there is no established 
322  predictive relationship between magnitude and timing of reductions in viral RNA 
323  shedding and the extent of clinical benefit of how a patient feels, functions, or survives. 
324  Additionally, the optimal sample size, timing, and methods for collection procedures 
325  have not been established and assays for clinically relevant virologic measurements have 
326  not been validated. In phase 3 treatment trials, virologic endpoints may be assessed as 
 
24 See Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19), 
available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html. 
 
25 C Karagiannidis, C Mostert, C Hentschker, T Voshaar, J Malzahn, G Schillinger, J Klauber, U Janssens, G Marx, 
S Weber-Carstens, S Kluge, M Pfeifer, L Grabenhenrich, T Welte, and R Busse, 2020, Case Characteristics, 
Resource Use, and Outcomes of 10021 Patients with COVID-19 Admitted to 920 German Hospitals: an 
Observational Study, Lancet Respir Med, 8(9):853862. 
 
9  Contains Nonbinding Recommendations 
327  secondary endpoints. Collection of virologic data and evaluation of activity against 
328  circulating variants and treatment-emergent resistance are important components of drug 
329  development for COVID-19 (see Appendix B and Appendix C). 
330   
331    For endpoints defined by events through or at a prespecified time point, the time point 
332  should be defined as number of days after randomization. The time window should be 
333  sufficiently long to ensure capture of important events related to patient status, treatment, 
334  and COVID-19 progression. 
335   
336  4.  Safety Considerations 
337   
338  Sponsors of drugs to treat COVID-19 should consider the following:  
339   
340    The size and composition of the safety database needed to support an indication for 
341  COVID-19 depends on factors such as the proposed population, the treatment effect, the 
342  drugs toxicity, and the extent of the prior clinical experience with the drug (and possibly 
343  with related drugs). For example, for drugs with a well-characterized safety profile with 
344  low toxicity, a more streamlined approach to data collection may be appropriate (e.g., 
345  limiting adverse event collection to serious adverse events, adverse events leading to 
346  discontinuation, and grade 3 and grade 4 adverse events).26 Conversely, for drugs that are 
347  less well characterized or repurposed agents known to be highly toxic (e.g., some 
348  oncologic drugs), a more detailed collection of safety data would be warranted. Sponsors 
349  are encouraged to discuss their proposed safety database with FDA early in the course of 
350  clinical development.   
351   
352    Sponsors may provide a standardized toxicity grading scale. For clinical trials in subjects 
353  with severe COVID-19 or subjects with serious comorbidities, examples of toxicity 
354  grading scales include those published by the National Institutes of Healths Division of 
355  AIDS27 and the National Cancer Institute.28 For trials evaluating mild-to-moderate 
356  COVID-19, an example grade scale can be found in the guidance for industry Toxicity 
357  Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
358  Vaccine Clinical Trials (September 2007).  
359   
360    Sponsors should address the potential for drug-drug interactions that could increase the 
361  risk for toxicities (caused by increased exposures of the investigational drug or the drug 
362  that it interacts with) and propose mitigation strategies. 
363   
 
26 See the guidance for industry E19 A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-
approval or Post-Approval Clinical Trials (December 2022). 
  
27 See the National Institutes of Healths Division of AIDS Adverse Event Grading Tables, available at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
 
28 See the National Cancer Institutes Common Terminology Criteria for Adverse Events, available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
10  Contains Nonbinding Recommendations 
364    Safety assessments (e.g., vital signs, laboratory studies, electrocardiograms) should be 
365  performed on a schedule commensurate with severity of illness and the identified 
366  potential risk of the study drug. 
367   
368    Sponsors should conduct safety reporting as outlined in FDA regulations29 and relevant 
369  guidance.30 
370   
371  5.  Statistical Considerations 
372   
373  Sponsors of drugs to treat COVID-19 should consider the following: 
374   
375    Sponsors should justify their assumptions in sample size calculations. The sample size 
376  should be large enough to provide a reliable answer to the safety and efficacy questions 
377  the trial is meant to address. 
378   
379    Sponsors are encouraged to consider the estimands31 of interest and to adequately define 
380  those estimands in both the protocol and the statistical analysis plan.  
381   
382    The primary efficacy analysis should be conducted in all randomized subjects. 

383   
384    For key efficacy endpoints in treatment trials, FDA generally recommends the 

385  following approaches for handling intercurrent events.32 For any alternative 
386  strategies, sponsors should justify that the estimand addresses a meaningful clinical 
387  question of interest and can be estimated with plausible assumptions.  
388   
389    Sponsors should use a composite variable strategy33 to handle death, with death 
390  taking a sufficiently unfavorable value. Death should not be considered a form of 
391  missing data. 
392   
393    Sponsors should also use the composite variable strategy for handling 
394  hospitalization in the outpatient population.  
395   
 
29 See 21 CFR 312.32. 
 
30 See the guidance for industry Safety Reporting Requirements for INDs and BA/BE Studies (December 2012). In 
addition, FDA has proposed relevant recommendations in the draft guidance for industry Safety Assessment for IND 
Safety Reporting. 
 
31 See the guidance for industry E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials (May 2021). 
 
32 Intercurrent events are events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. See ICH E9(R1). 
 
33 Ibid. 
 
11  Contains Nonbinding Recommendations 
396    Sponsors should use a treatment policy strategy34 for other intercurrent events. 
397   
398    To improve the precision of treatment effect estimation and inference, sponsors should 
399  consider adjusting for prespecified prognostic baseline covariates (e.g., age, baseline 
400  severity, comorbidities, baseline medications, and COVID-19 vaccination status) in the 
401  primary efficacy analysis and should propose methods of covariate adjustment. For 
402  example, for a binary endpoint, methods can be used to gain precision in the evaluation 
403  of the difference in proportions.35,36 
404   
405    Restricting analyses to a subset of patients defined by a post-randomization variable (e.g., 
406  intensive care unit admission, ventilator use) can lead to results that are difficult to 
407  interpret. The analysis set or sets to be used in the statistical analyses for any key efficacy 
408  endpoint should be defined according to measurements and characteristics that can be 
409  observed at baseline. 
410   
411    If a treatment trial enrolls a mixture of subjects with different baseline severity levels, 
412  baseline medication use, and/or vaccination statuses, sponsors should conduct subgroup 
413  or interaction analyses to assess for differential treatment effects. Sponsors should also 
414  provide analyses describing concomitant medication use and changes in vaccination 
415  status during the trial overall and by treatment arm.  
416   
417    Sponsors should submit a statistical analysis plan for review before any unblinding of 
418  data. In addition to the statistical methods provided in the protocol, the statistical analysis 
419  plan for a trial should contain detailed information on each primary and secondary 
420  endpoint; the main, supplemental, and sensitivity analysis methods of key efficacy 
421  endpoints; the multiple testing procedure for controlling the overall type I error rate, if 
422  applicable; and methods for handling missing data. If applicable, sponsors should 
423  prespecify the interim analysis procedures (e.g., statistical methods, boundaries) and 
424  should provide in a DMC charter detailed procedures and discussions of methods to 
425  maintain trial integrity (e.g., unblinded personnel, firewalls).   
426   
427  B.  Prevention Trials 
428   
429    The availability of vaccines and timing of vaccine administration to prevent COVID-19 
430  has implications for the design and conduct of trials evaluating drugs for the prevention 
431  of COVID-19. FDA recommends that sponsors contact the Agency early on in the 
432  planning of such trials. 
433   
 
34 Ibid. 
 
35 JA Steingrimsson, DF Hanley, and M Rosenblum, 2017, Improving Precision by Adjusting for Prognostic 
Baseline Variables in Randomized Trials With Binary Outcomes, Without Regression Model Assumptions, 
Contemp Clin Trials, 54:1824. 
 
36 T Ye, M Bannick, Y Yi, and J Shao, 2023, Robust Variance Estimation for Covariate-Adjusted Unconditional 
Treatment Effect in Randomized Clinical Trials With Binary Outcomes, Stat Theory and Relat Fields, 7(2):159163. 
12  Contains Nonbinding Recommendations 
434    In prevention trials, the primary endpoint should be the occurrence of laboratory-
435  confirmed SARS-CoV-2 infection (with or without symptoms) or SARS-CoV-2 infection 
436  with symptoms (i.e., COVID-19) through a prespecified time point. 
437   
438    Sponsors are encouraged to evaluate both laboratory-confirmed SARS-CoV-2 

439  infection (with or without symptoms) and SARS-CoV-2 infection with symptoms 
440  (i.e., COVID-19) when possible. 
441   
442    Ascertaining whether COVID-19 is milder in persons receiving drugs for the 

443  prevention of COVID-19 compared with persons not receiving such therapies is of 
444  interest. Sponsors should collect clinical outcome data (e.g., hospitalization) and data 
445  on symptoms to support such analyses. 
446   
447    Sponsors should also conduct SARS-CoV-2 antibody testing at baseline and at later time 
448  points to detect serologic evidence of infection in prevention trials, which may identify 
449  cases of asymptomatic infection or infections that were otherwise undetected by virologic 
450  testing.  
451   
452    For pre- or post-exposure prevention trials, protocols should include clear plans and 
453  testing algorithms for detecting SARS-CoV-2 infection. Protocols should indicate the 
454  specific viral assay(s) to be used and should describe assay performance characteristics, 
455  including any known or predicted impact of emerging SARS-CoV-2 variants on assay 
456  performance. 
13  Contains Nonbinding Recommendations 
457  APPENDIX A 
458   
459  EXAMPLES OF BASELINE SEVERITY CATEGORIZATION 
460   
461  SARS-CoV-2 infection without symptoms 
462   
463    Positive testing by virologic test (i.e., a nucleic acid amplification test or an antigen test)  
464   
465    No symptoms 
466   
467  Mild COVID-19 
468   
469    Positive testing by virologic test (i.e., a nucleic acid amplification test or an antigen test) 
470   
471    Symptoms of mild illness with COVID-19 that could include fever, cough, sore throat, 
472  malaise, headache, muscle pain, nausea, vomiting, diarrhea, and loss of taste or smell, 
473  without shortness of breath or dyspnea 
474   
475    No clinical signs indicative of Moderate, Severe, or Critical Severity 
476   
477  Moderate COVID-19 
478   
479    Positive testing by virologic test (i.e., a nucleic acid amplification test or an antigen test) 
480   
481    Symptoms of moderate illness with COVID-19, which could include any symptom of 
482  mild illness or shortness of breath with exertion 
483   
484    Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate  
485  20 breaths per minute, heart rate  90 beats per minute; with saturation of oxygen (SpO ) 
2
486  > 93% on room air at sea level1 
487   
488    No clinical signs indicative of Severe or Critical Severity 
489   
490  Severe COVID-19 
491   
492    Positive testing by virologic test (i.e., a nucleic acid amplification test or an antigen test)  
493   
494    Symptoms suggestive of severe systemic illness with COVID-19, which could include 
495  any symptom of moderate illness or shortness of breath at rest, or respiratory distress  
496   
 
1 Although pulse oximetry is useful for estimating blood oxygen levels, pulse oximeters have limitations and a risk 
of inaccuracy under certain circumstances that should be considered. See FDAs Pulse Oximeter Accuracy and 
Limitations: FDA Safety Communication, 2022, available at https://www.fda.gov/medical-devices/safety-
communications/pulse-oximeter-accuracy-and-limitations-fda-safety-communication. 
14  Contains Nonbinding Recommendations 
497    Clinical signs indicative of severe systemic illness with COVID-19, such as respiratory 
498  rate  30 per minute, heart rate  125 per minute, SpO   93% on room air at sea level or 
2
499  PaO /FiO  < 300 
2 2
500   
501    No clinical criteria for Critical Severity 
502   
503  Critical COVID-19 
504   
505    Positive testing by virologic test (i.e., a nucleic acid amplification test or an antigen test) 
506   
507    Evidence of critical illness, defined by at least one of the following: 
508   
509    Respiratory failure defined as requiring at least one of the following:  
510   
511    Endotracheal intubation and mechanical ventilation, oxygen delivered by high-
512  flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal 
513  cannula at flow rates > 20 L/min with fraction of delivered oxygen  0.5), 
514  noninvasive positive pressure ventilation, extracorporeal membrane oxygenation  
515   
516    Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure < 
517  60 mm Hg or requiring vasopressors) 
518   
519    Multi-organ dysfunction/failure 
520   
521   
15  Contains Nonbinding Recommendations 
522  APPENDIX B 
523   
524  DRUG RESISTANCE ANALYSIS 
525   
526  The drug resistance analysis plan should include the following: 
527   
528    Characterize the antiviral activity of the drug in cell culture assays against a panel of 
529  geographically, temporally, and phylogenetically distinct SARS-CoV-2 isolates, 
530  including isolates representative of the most common variants currently circulating 
531  globally. 
532   
533    Evaluate combination antiviral activity relationships in cell culture assays between 
534  candidate drugs planned for use in a combination regimen, or between the candidate 
535  drug(s) and any other authorized or approved drugs if they are anticipated to be used in 
536  combination. 
537   
538    Select for viruses resistant to the drug in cell culture assays and characterize drug-
539  resistant viruses genotypically and phenotypically to support drug resistance and cross-
540  resistance analyses. These studies should be conducted under appropriate 
541  biocontainment1 or consider using a surrogate or recombinant virus expressing the 
542  SARS-CoV-2 target protein. 
543   
544    Identify reported SARS-CoV-2 amino acid polymorphisms in the drug target and 
545  describe their prevalence and rates of emergence in publicly available viral sequence 
546  databases. If the drug has been co-crystalized with the viral target protein, identify 
547  polymorphisms in the viral target at amino acid positions that are within 5 angstroms of 
548  the drug structure.  
549   
550    Include detailed plans in clinical protocols to (a) characterize the impact of SARS-CoV-2 
551  genetic variability on clinical and virologic outcomes (i.e., baseline resistance analyses) 
552  and (b) identify SARS-CoV-2 genetic changes associated with treatment (i.e., treatment-
553  emergent resistance analyses).  
554   
555    Characterize the impact of specific amino acid variants in the drug target on drug activity 
556  using cell culture phenotype assays. If a pseudotyped virus-like particle assay or other 
557  surrogate assay is used, conduct validation studies showing that the surrogate assay yields 
558  results that are consistent with those obtained with authentic virus regarding the relative 
559  impact of different variants. 
 
1 For biosafety considerations from the National Institutes of Health, 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 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. 
16  Contains Nonbinding Recommendations 
560   
561    Assess the potential for cross-resistance with other drugs with the same target or similar 
562  mechanism of action based on results of genotypic and phenotypic assays. 
563   
564    Monitor continuously for emerging SARS-CoV-2 variants and evaluate phenotypically 
565  any specific variants in the drug target that are becoming prevalent or could potentially 
566  impact drug activity. 
567   
568    Conduct proof of principle studies in small animal models given the limited availability 
569  of nonhuman primates. 
570   
571    Identify known human genetic polymorphisms and characterize their potential impact on 
572  drug activity in nonclinical and/or clinical studies if the drug targets a host factor. The 
573  types and frequencies of polymorphisms in different racial/ethnic groups should be 
574  provided to FDA. Samples for resistance assessments should be collected in clinical trials 
575  for host targeting antivirals as resistance can occur with these drugs. 
576   
577    Follow established FDA guidance for submission of next generation sequencing data 
578  generated from clinical trials.2 Consult with the appropriate review division for additional 
579  advice on collection and submission of drug resistance data. 
580   
 
2 See the guidance for industry Submitting Next Generation Sequencing Data to the Division of Antiviral Products 
(July 2019). 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. 
17  Contains Nonbinding Recommendations 
581  APPENDIX C 
582   
583  IMPACT OF DRUGS ON VIRAL SHEDDING AND IMMUNE RESPONSES 
584   
585  Clinical trial protocols should include plans to characterize the impact of drugs on viral shedding 
586  and immune responses as follows: 
587   
588    Indicate specific time points and clinical specimens to be collected and analyzed.   
589   
590    Describe the specific types of respiratory samples to be collected (e.g., nasopharyngeal 
591  swabs, nasal mid-turbinate swab, saliva) and the collection procedures. Refer to current 
592  Centers for Disease Control and Prevention guidelines for specific definitions of 
593  specimen types and additional recommendations.1   
594   
595    Collect and analyze the same specimen type(s) for baseline and subsequent time points 
596  when assessing the impact of treatment on viral shedding as assays may have varying 
597  sensitivity or performance for different respiratory specimen types.   
598   
599    Collect nonrespiratory specimens (e.g., blood, bronchoalveolar lavage fluid) for virologic 
600  analyses when feasible to assess the impact of antiviral treatment on virus replication in 
601  other compartments, which may play a role in disease pathogenesis.   
602   
603    Include an assessment of viral RNA levels (e.g., quantitative RT-PCR) for viral shedding 
604  analyses. Sponsors are encouraged to assess viral RNA shedding both quantitatively (e.g., 
605  log  decline from baseline at a specific time point) and qualitatively (e.g., detected or not 
10
606  detected at a specific time point). Indicate the specific viral RNA assay(s) to be used and 
607  whether they have received FDA emergency use authorization or approval.   
608   
609    Consider conducting virus infectivity assays to characterize the impact of treatment on 
610  shedding of cell culture infectious virus. Such assays should be conducted under 
611  appropriate biocontainment.2  
612   
613    Describe assay performance characteristics, including any known or predicted impact of 
614  emerging SARS-CoV-2 variants on assay performance. 
615   
 
1 See the Centers for Disease Control and Prevention Interim Guidelines for Collecting and Handling of Clinical 
Specimens for COVID-19 Testing, available at https://www.cdc.gov/coronavirus/2019-ncov/lab/guidelines-clinical-
specimens.html. 
 
2
 For biosafety considerations from the National Institutes of Health, 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. 
18  Contains Nonbinding Recommendations 
616    Characterize the impact of treatments on markers of inflammation (e.g., pro-
617  inflammatory cytokines) and on the development of anti-SARS-CoV-2 immune 
618  responses when possible. 
619   
620    Consider conducting these laboratory assessments in central laboratories or include 
621  internal assay references to minimize the potential introduction of variability attributable 
622  to assessments being conducted in different laboratories.    
623   
624   
19