COVID-19: Developing Drugs and Biological Products for Treatment or Prevention: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
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................................................................................................................ 4
3. Efficacy Endpoints ........................................................................................................................... 7
4. Safety Considerations ...................................................................................................................... 9
5. Statistical Considerations .............................................................................................................. 10
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	1
Treatment or Prevention	2
Guidance for Industry1
3
4
5
6
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on	7
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You	8
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.	9
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the	10
title page	11
12
13
14
I. 	INTRODUCTION	15
16
The purpose of this guidance is to assist sponsors in the clinical development of drugs2 for the	17
treatment or prevention of COVID-19. This guidance describes FDA’s current recommendations	18
for phase 2 and phase 3 trials with a focus on trial population, trial design, efficacy endpoints,	19
safety considerations, and statistical considerations. There may be additional considerations for	20
some biological products (e.g., cellular and gene therapies and blood products), so FDA	21
encourages sponsors to reach out to the applicable review division as appropriate.	22
23
The development of drugs for the treatment of Long COVID-19, preventative vaccines3 and	24
convalescent plasma4 is not within the scope of this guidance.	25
26
FDA is implementing this guidance without prior public comment because the Agency has	27
determined that prior public participation is not feasible or appropriate (see 21 CFR 10.115(g)(2)	28
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).

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and (g)(3). FDA made this determination because although the COVID-19-related public health	29
emergency under section 319 has expired, SARS-CoV-2 continues to circulate, COVID-19	30
remains a serious health risk for some individuals, and there is a need to ensure that sponsors are	31
aware of FDA’s recommendations to facilitate timely development of drugs and biological	32
products for treatment and prevention of COVID-19. This guidance document is being	33
implemented immediately, but it remains subject to comment in accordance with the Agency’s	34
good guidance practices.	35
36
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	37
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed	38
only as recommendations, unless specific regulatory or statutory requirements are cited. The	39
use of the word should in Agency guidances means that something is suggested or	40
recommended, but not required.	41
42
43
II. 	BACKGROUND	44
45
COVID-19, the disease caused by the SARS-CoV-2 virus, can range from mild to severe or	46
critical disease, the latter including pneumonia, severe acute respiratory syndrome, multi-organ	47
failure, and death. Additionally, the SARS-CoV-2 virus can cause asymptomatic infection.	48
Clinical management includes the use of preventative vaccines and therapeutic agents (e.g.,	49
direct antivirals, immunomodulators) and supportive care, such as supplemental oxygen,	50
mechanical ventilation, and extracorporeal membrane oxygenation.	51
52
53
III. 	DISCUSSION	54
55
A. 	Treatment Trials	56
57
1. 	Population	58
59
Sponsors of drugs to treat COVID-19 should consider the following:	60
61
• 	The enrolled population should reflect the intended use of the product. For example:	62
63
– 	Non-hospitalized individuals at standard risk of progression to serious disease	64
– 	Non-hospitalized individuals at high risk of progression to serious disease	65
– 	Hospitalized individuals requiring supplemental oxygen	66
– 	Hospitalized individuals with respiratory failure	67
68
• 	For treatment trials, sponsors should document diagnosis of laboratory-confirmed SARS-	69
CoV-2 as well as the duration of symptoms before treatment.	70
71
• 	For treatment trials, FDA recommends that sponsors categorize the baseline severity of	72
COVID-19 in the enrolled population. The criteria used to describe baseline disease	73

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severity should incorporate objective measures. Examples of disease severity criteria are	74
provided in Appendix A.	75
76
• 	Clinical trials intended to demonstrate prevention of serious outcomes, including	77
hospitalization or death, should include groups of persons at high risk of progression to	78
severe disease.	79
80
• 	Age is one of the strongest risk factors for severe COVID-19 outcomes. To the fullest	81
extent possible, older adults, including individuals 75 years of age and older, should be	82
represented in relevant clinical trials. Sponsors should consider conducting trials in	83
nursing homes or other eldercare facilities.	84
85
• 	Individuals from underrepresented racial and ethnic groups should be represented in	86
clinical trials. Sponsors should select clinical study site locations to facilitate enrollment	87
of a representative study population.	88
89
• 	Studies to characterize the effect of extrinsic factors (e.g., drug-drug interactions) and	90
intrinsic factors (e.g., renal impairment or hepatic impairment) on the pharmacokinetics	91
of a drug should be conducted early in development to inform the management of drug-	92
drug interactions and inclusion of individuals with renal and/or hepatic impairment in	93
clinical trials as appropriate. Sponsors should consider recommendations in relevant	94
guidances for industry.5	
95
96
• 	The principles outlined in this document can be used to guide drug development for	97
children and for pregnant and lactating women. There is a need to generate clinical trial	98
data to inform the use of drugs in these populations.	99
100
– 	Because COVID-19 during pregnancy may increase the risk of severe symptoms and	101
preterm birth, sponsors should ensure that adequate nonclinical studies have been	102
completed so that pregnant women can be enrolled in phase 3 (efficacy) clinical	103
trials.6	
104
105
– 	FDA encourages enrolling lactating women in phase 3 (efficacy) clinical trials.	106
107
5 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 FDA’s 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 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
FDA’s current thinking on this topic.

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– 	Children should not be categorically excluded from clinical trials of investigational	108
COVID-19 products in which there is a prospect for direct benefit.7	
109
110
 	Sponsors are encouraged to discuss pediatric drug development with FDA early in	111
the course of clinical development, including the potential for extrapolation of	112
efficacy data from studies in adults, appropriate pharmacokinetic trials in	113
pediatric subjects to support dose selection, and the recommended size of the	114
preapproval safety database in children. In addition, disease severity classification	115
should reflect age-appropriate norms, as applicable. Decisions on the timing of	116
initiating pediatric studies depend on several factors, including but not limited to	117
the amount of available clinical and/or nonclinical safety data for the drug. For	118
example, if dosing recommendations for a drug are the same for adults and	119
adolescents8 and there is a prospect of direct benefit, then adolescents should be	120
included in the initial phase 3 clinical trials.	121
122
 	Sponsors are encouraged to submit an initial pediatric study plan as soon as	123
practicable.9	
124
125
 	Under the Pediatric Research Equity Act, all applications for new active	126
ingredients (which include new salts and new fixed combinations), new	127
indications, new dosage forms, new dosing regimens, or new routes of	128
administration are required to contain an assessment of the safety and	129
effectiveness of the product for the claimed indication or indications in pediatric	130
populations unless this requirement is waived, deferred, or inapplicable.10 FDA	131
intends to work with sponsors to reach agreement on the initial pediatric study	132
plan and any pediatric trial protocols as quickly as possible to avoid any	133
unnecessary delays in the initiation of trials or submission of any marketing	134
application.	135
136
2. 	Trial Design and Conduct	137
138
Sponsors of drugs to treat COVID-19 should consider the following:	139
140
• 	FDA strongly recommends that drugs to treat COVID-19 be evaluated in randomized,	141
controlled, double-blind clinical trials.	142
143
7 For additional safeguards for children in clinical investigations, see 21 CFR part 50, subpart D.
8 For the purposes of this guidance, adolescents are defined as age 12 to younger than 18 years of age.
9 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).
10 See 21 U.S.C. 355c.

Contains Nonbinding Recommendations
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– 	Typically, trials should be designed as placebo-controlled superiority studies. An add-	144
on placebo design (i.e., the investigational agent or placebo added on to standard of	145
care) may be necessary to maintain equipoise.	146
147
– 	For agents with a similar mechanism of action as the background standard of care	148
(e.g., direct antiviral agent as the investigational agent when the standard of care is	149
also a direct antiviral agent), an active-comparator controlled study design may be	150
considered. A superiority trial design or noninferiority design11 may be appropriate.	151
152
• 	Sponsors are encouraged to use quantitative clinical pharmacology approaches that	153
leverage all available information for selection of dosing regimen(s) to be evaluated in	154
clinical trials.12	
155
156
• 	Sponsors should plan to collect baseline vaccination status, changes in vaccination status	157
during the trial, and baseline and concomitant medication use, including COVID-19	158
standard of care therapies.	159
160
• 	Sponsors should address the possibility of drug and COVID-19 vaccine interactions for	161
drugs that may interfere with vaccine effectiveness (i.e., monoclonal antibodies targeting	162
the vaccine antigen). Sponsors should consult with the Agency early in the development	163
program for such drugs.	164
165
• 	SARS-CoV-2 has and continues to evolve, resulting in the emergence of SARS-CoV-2	166
with genetic changes that may impact the effectiveness of antiviral drugs. Sponsors	167
should determine the antiviral activity (EC50 and EC90 values) of their drug against	168
currently predominant and emerging U.S. variants.	169
170
• 	Using an antiviral drug to treat COVID-19 may contribute to the emergence of viruses	171
with reduced susceptibility to the drug or to other approved or investigational drugs.	172
Sponsors should characterize drug resistance pathways and the potential for cross-	173
resistance to other drugs using both nonclinical and clinical studies. Details regarding	174
drug resistance analysis are provided in Appendix B. Sponsors should also refer to the	175
guidance for industry Antiviral Product Development — Conducting and Submitting	176
Virology Studies to the Agency (June 2006).	177
178
• 	Clinical trial protocols should include plans to characterize the impact of drugs on viral	179
shedding and immune responses as described in Appendix C.	180
181
• 	Decentralized clinical trials (DCTs) may play a role in COVID-19 drug development	182
programs. Sponsors considering a DCT should plan early discussions with the	183
11 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).
12 See the guidances for industry Population Pharmacokinetics (February 2022) and Exposure-Response
Relationships — Study Design, Data Analysis, and Regulatory Applications (May 2003).

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appropriate review division, as a DCT may introduce additional complexities related to	184
feasibility, design, implementation, and analysis of the data.13,14	
185
186
– 	Sponsors should consider several factors when determining if conducting a DCT is	187
appropriate, selecting the location of a trial visit, and/or selecting personnel	188
performing an assessment. These factors include the following:	189
190
 	The severity of COVID-19	191
192
 	The nature of the investigational product (e.g., ease of administration, safety	193
profile, stability profile, storage conditions)	194
195
 	The type of trial procedure or assessment (e.g., administration of investigational	196
product, clinical laboratory assessment, clinical outcome assessment, or adverse	197
event assessment/follow-up)	198
199
• 	Sponsors considering the use of adaptive design elements in their clinical trial should	200
review the guidance for industry Adaptive Designs for Clinical Trials of Drugs and	201
Biologics (November 2019). If a trial incorporates any adaptations to the sample size,	202
dosing arms, or other design features, sponsors should prospectively plan the design in a	203
manner to ensure control of the type I error rate and reliable treatment effect estimation.	204
205
• 	FDA strongly discourages disseminating data from ongoing trials. Knowledge of	206
accumulating data by trial investigators and subjects can adversely affect subject accrual,	207
adherence, and retention, as well as endpoint assessment, compromising the ability of the	208
trial to reliably achieve its objective in a timely manner. Issues with trial conduct caused	209
by knowledge of interim results are difficult to predict and generally impossible to adjust	210
for in statistical analyses. Therefore, releasing interim results could have ramifications on	211
the integrity of the ongoing trial and the ability to collect reliable and interpretable data	212
needed to support regulatory decision-making. If sponsors intend to conduct interim	213
analyses, FDA recommends they prospectively plan these analyses and incorporate	214
processes to maintain the integrity of the trial (e.g., using an independent DMC).15 FDA	215
recognizes there may be exceptional circumstances in which a sponsor determines it	216
needs to disseminate results for safety or other reasons. In such situations, the sponsor is	217
strongly encouraged to discuss with FDA before releasing such results.	218
219
• 	FDA encourages sponsors to incorporate prospectively planned criteria to stop the trial	220
for futility (lack of efficacy) or harm in any confirmatory trial. The stopping criteria	221
13 See the draft guidance for industry Decentralized Clinical Trials for Drugs, Biological Products, and Devices
(May 2023). When final, this guidance will represent the FDA’s current thinking on this topic.
14 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 FDA’s
current thinking on this topic.
15 See guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics.

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should aim to ensure a high probability of halting the trial if the drug is harmful (e.g.,	222
associated with a higher risk of death), a reasonable probability of halting the trial if the	223
drug is ineffective, and a high probability of continuing the trial if the drug is effective.	224
225
• 	FDA encourages sponsors to use an independent, external data monitoring committee	226
(DMC) to ensure subject safety and trial integrity.	227
228
– 	Sponsors should submit the DMC charter to FDA before enrolling subjects.	229
230
– 	Sponsors should ensure there will be appropriate DMC monitoring to safeguard the	231
welfare of subjects, accounting for important factors such as the expected enrollment	232
rate, the expected lag time to analyze interim data for DMC meetings, and the	233
frequency of DMC meetings.16	
234
235
• 	The trial should aim to minimize missing data. The protocol should distinguish between	236
discontinuation from the study drug and withdrawal from study assessments. Trial	237
subjects may choose to discontinue treatment during the trial for various reasons, such as	238
experiencing adverse events or perceived lack of efficacy. Unless the subject withdraws	239
consent,17 sponsors should encourage subjects who discontinue therapy to remain in the	240
study and to continue follow-up for key safety and efficacy assessments. Virtual follow-	241
up is acceptable, if appropriate, and the aim should be to record vital status for all	242
subjects.	243
244
• 	Applicable clinical trials need to be registered at www.ClinicalTrials.gov as required by	245
42 CFR part 11. FDA encourages responsible parties to promptly update	246
www.clinicaltrial.gov with the results of completed trials given their public health	247
importance.	248
249
3. 	Efficacy Endpoints	250
251
Sponsors of drugs to treat COVID-19 should consider the following:	252
253
• 	The drug development program should evaluate the effect of the investigational drug	254
relative to placebo or an active comparator on clinically meaningful aspects of the	255
disease. The relevance and appropriateness of measures may depend on factors such as	256
the mechanism of action of the drug, the population studied, the clinical setting, the phase	257
of drug development, and/or baseline disease severity (see Appendix A).	258
259
• 	Examples of important clinical outcome measures in treatment trials include the	260
following:	261
262
16 See the guidance for industry Establishment and Operation of Clinical Trial Data Monitoring Committees (March
2006).
17 Withdrawal of consent refers to a subject’s 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.

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– 	All-cause mortality.	263
264
– 	Respiratory failure (i.e., need for mechanical ventilation, extracorporeal membrane	265
oxygenation, noninvasive positive pressure ventilation, or high-flow nasal cannula	266
oxygen delivery).	267
268
– 	Need for invasive mechanical ventilation.	269
270
– 	Need for hospitalization.	271
272
– 	Objective measures of sustained improvement (e.g., return to room air or baseline	273
oxygen requirement).	274
275
– 	Sustained symptom alleviation or resolution. For trials evaluating non-hospitalized	276
patients, this can be defined as occurring when no key COVID-19-related symptom	277
scored higher than a prespecified threshold over a clinically meaningful time period	278
(as documented using a patient-reported outcome instrument).18	
279
280
– 	Clinical status using an ordinal scale that incorporates multiple clinical outcomes of	281
interest ordered by their clinical importance.	282
283
• 	The choice, time frame, and interpretation of endpoints may differ depending on the	284
population evaluated in the trial. For example,	285
286
– 	In a trial in severe and/or critically ill patients, examples of appropriate endpoints	287
could be	288
289
 	All-cause mortality at an appropriate time point (e.g., at least 28 days for	290
hospitalized noncritically ill patients, 60 days for critically ill patients19)	291
292
 	Proportion of patients alive and free of respiratory failure at an appropriate time	293
point (e.g., at least 28 days for hospitalized noncritically ill patients, 60 days for	294
critically ill patients)	295
296
– 	In an outpatient treatment trial, examples of appropriate endpoints could be	297
18 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.
19 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):853–862.

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298
 	Proportion of patients progressing to hospitalization or death by an appropriate	299
time point (e.g., at least 28 days).	300
301
 	Time to sustained symptom alleviation or resolution assessed over an appropriate	302
duration.	303
304
• 	For primary endpoints other than all-cause mortality, a treatment effect could be driven	305
by nonmortality components (e.g., hospitalization) despite increased mortality while on	306
the investigational drug. Therefore, analyses of all-cause mortality will be important	307
regardless of the selected primary endpoint. Additionally, powering the trial based on	308
other endpoints, such as time to sustained recovery, may result in less precision in the	309
assessment of all-cause mortality attributable to a smaller patient sample size. Depending	310
on the population and mechanism of action of the investigational drug(s), additional	311
consideration may be needed to determine if the sample size is sufficient to provide an	312
adequate assessment of mortality.	313
314
• 	In their endpoint definition, sponsors should address the occurrence of relapses to ensure	315
adequate assessment of the durability of response.	316
317
• 	In phase 2 treatment trials, a virologic measure may be acceptable as a primary endpoint	318
to support progression to a phase 3 clinical endpoint trial. However, virologic endpoints	319
are not appropriate as primary endpoints in a phase 3 trial because there is no established	320
predictive relationship between magnitude and timing of reductions in viral RNA	321
shedding and the extent of clinical benefit of how a patient feels, functions, or survives.	322
Additionally, the optimal sample size, timing, and methods for collection procedures	323
have not been established and assays for clinically relevant virologic measurements have	324
not been validated. In phase 3 treatment trials, virologic endpoints may be assessed as	325
secondary endpoints. Collection of virologic data and evaluation of activity against	326
circulating variants and treatment-emergent resistance are important components of drug	327
development for COVID-19 (see Appendix B and Appendix C).	328
329
• 	For endpoints defined by events through or at a prespecified time point, the time point	330
should be defined as number of days after randomization. The time window should be	331
sufficiently long to ensure capture of important events related to patient status, treatment,	332
and COVID-19 progression.	333
334
4. 	Safety Considerations	335
336
Sponsors of drugs to treat COVID-19 should consider the following:	337
338
• 	The size and composition of the safety database needed to support an indication for	339
COVID-19 depends on factors such as the proposed population, the treatment effect, the	340
drug’s toxicity, and the extent of the prior clinical experience with the drug (and possibly	341
with related drugs). For example, for drugs with a well-characterized safety profile with	342
low toxicity, a more streamlined approach to data collection may be appropriate (e.g.,	343

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limiting adverse event collection to serious adverse events, adverse events leading to	344
discontinuation, and grade 3 and grade 4 adverse events).20 Conversely, for drugs that are	345
less well characterized or repurposed agents known to be highly toxic (e.g., some	346
oncologic drugs), a more detailed collection of safety data would be warranted. Sponsors	347
are encouraged to discuss their proposed safety database with FDA early in the course of	348
clinical development.	349
350
• 	Sponsors may provide a standardized toxicity grading scale. For clinical trials in subjects	351
with severe COVID-19 or subjects with serious comorbidities, examples of toxicity	352
grading scales include those published by the National Institutes of Health’s Division of	353
AIDS21 and the National Cancer Institute.22 For trials evaluating mild-to-moderate	354
COVID-19, an example grade scale can be found in the guidance for industry Toxicity	355
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive	356
Vaccine Clinical Trials (September 2007).	357
358
• 	Sponsors should address the potential for drug-drug interactions that could increase the	359
risk for toxicities (caused by increased exposures of the investigational drug or the drug	360
that it interacts with) and propose mitigation strategies.	361
362
• 	Safety assessments (e.g., vital signs, laboratory studies, electrocardiograms) should be	363
performed on a schedule commensurate with severity of illness and the identified	364
potential risk of the study drug.	365
366
• 	Sponsors should conduct safety reporting as outlined in FDA regulations23 and relevant	367
guidance.24	
368
369
5. 	Statistical Considerations	370
371
Sponsors of drugs to treat COVID-19 should consider the following:	372
373
• 	Sponsors should justify their assumptions in sample size calculations. The sample size	374
should be large enough to provide a reliable answer to the safety and efficacy questions	375
the trial is meant to address.	376
20 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).
21 See the National Institutes of Health’s Division of AIDS Adverse Event Grading Tables, available at
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables.
22 See the National Cancer Institute’s Common Terminology Criteria for Adverse Events, available at
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
23 See 21 CFR 312.32.
24 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.

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377
• 	Sponsors are encouraged to consider the estimands25 of interest and to adequately define	378
those estimands in both the protocol and the statistical analysis plan.	379
380
– 	The primary efficacy analysis should be conducted in all randomized subjects.	381
382
– 	For key efficacy endpoints in treatment trials, FDA generally recommends the	383
following approaches for handling intercurrent events.26 For any alternative	384
strategies, sponsors should justify that the estimand addresses a meaningful clinical	385
question of interest and can be estimated with plausible assumptions.	386
387
 	Sponsors should use a composite variable strategy27 to handle death, with death	388
taking a sufficiently unfavorable value. Death should not be considered a form of	389
missing data.	390
391
 	Sponsors should also use the composite variable strategy for handling	392
hospitalization in the outpatient population.	393
394
 	Sponsors should use a treatment policy strategy28 for other intercurrent events.	395
396
• 	To improve the precision of treatment effect estimation and inference, sponsors should	397
consider adjusting for prespecified prognostic baseline covariates (e.g., age, baseline	398
severity, comorbidities, baseline medications, and COVID-19 vaccination status) in the	399
primary efficacy analysis and should propose methods of covariate adjustment. For	400
example, for a binary endpoint, methods can be used to gain precision in the evaluation	401
of the difference in proportions.29,30	
402
403
• 	Restricting analyses to a subset of patients defined by a post-randomization variable (e.g.,	404
intensive care unit admission, ventilator use) can lead to results that are difficult to	405
interpret. The analysis set or sets to be used in the statistical analyses for any key efficacy	406
endpoint should be defined according to measurements and characteristics that can be	407
observed at baseline.	408
25 See the guidance for industry E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and
Sensitivity Analysis in Clinical Trials (May 2021).
26 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).
27 Ibid.
28 Ibid.
29 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, 54:18–24.
30 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):159–163.

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12
409
• 	If a treatment trial enrolls a mixture of subjects with different baseline severity levels,	410
baseline medication use, and/or vaccination statuses, sponsors should conduct subgroup	411
or interaction analyses to assess for differential treatment effects. Sponsors should also	412
provide analyses describing concomitant medication use and changes in vaccination	413
status during the trial overall and by treatment arm.	414
415
• 	Sponsors should submit a statistical analysis plan for review before any unblinding of	416
data. In addition to the statistical methods provided in the protocol, the statistical analysis	417
plan for a trial should contain detailed information on each primary and secondary	418
endpoint; the main, supplemental, and sensitivity analysis methods of key efficacy	419
endpoints; the multiple testing procedure for controlling the overall type I error rate, if	420
applicable; and methods for handling missing data. If applicable, sponsors should	421
prespecify the interim analysis procedures (e.g., statistical methods, boundaries) and	422
should provide in a DMC charter detailed procedures and discussions of methods to	423
maintain trial integrity (e.g., unblinded personnel, firewalls).	424
425
B. 	Prevention Trials	426
427
• 	The availability of vaccines and timing of vaccine administration to prevent COVID-19	428
has implications for the design and conduct of trials evaluating drugs for the prevention	429
of COVID-19. FDA recommends that sponsors contact the Agency early on in the	430
planning of such trials.	431
432
• 	In prevention trials, the primary endpoint should be the occurrence of laboratory-	433
confirmed SARS-CoV-2 infection (with or without symptoms) or SARS-CoV-2 infection	434
with symptoms (i.e., COVID-19) through a prespecified time point.	435
436
– 	Sponsors are encouraged to evaluate both laboratory-confirmed SARS-CoV-2	437
infection (with or without symptoms) and SARS-CoV-2 infection with symptoms	438
(i.e., COVID-19) when possible.	439
440
– 	Ascertaining whether COVID-19 is milder in persons receiving drugs for the	441
prevention of COVID-19 compared with persons not receiving such therapies is of	442
interest. Sponsors should collect clinical outcome data (e.g., hospitalization) and data	443
on symptoms to support such analyses.	444
445
• 	Sponsors should also conduct SARS-CoV-2 antibody testing at baseline and at later time	446
points to detect serologic evidence of infection in prevention trials, which may identify	447
cases of asymptomatic infection or infections that were otherwise undetected by virologic	448
testing.	449
450
• 	For pre- or post-exposure prevention trials, protocols should include clear plans and	451
testing algorithms for detecting SARS-CoV-2 infection. Protocols should indicate the	452
specific viral assay(s) to be used and should describe assay performance characteristics,	453

Contains Nonbinding Recommendations
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including any known or predicted impact of emerging SARS-CoV-2 variants on assay	454
performance.	455

Contains Nonbinding Recommendations
14
APPENDIX A	456
457
EXAMPLES OF BASELINE SEVERITY CATEGORIZATION	458
459
SARS-CoV-2 infection without symptoms	460
461
• 	Positive testing by virologic test (i.e., a nucleic acid amplification test or an antigen test)	462
463
• 	No symptoms	464
465
Mild COVID-19	466
467
• 	Positive testing by virologic test (i.e., a nucleic acid amplification test or an antigen test)	468
469
• 	Symptoms of mild illness with COVID-19 that could include fever, cough, sore throat,	470
malaise, headache, muscle pain, nausea, vomiting, diarrhea, and loss of taste or smell,	471
without shortness of breath or dyspnea	472
473
• 	No clinical signs indicative of Moderate, Severe, or Critical Severity	474
475
Moderate COVID-19	476
477
• 	Positive testing by virologic test (i.e., a nucleic acid amplification test or an antigen test)	478
479
• 	Symptoms of moderate illness with COVID-19, which could include any symptom of	480
mild illness or shortness of breath with exertion	481
482
• 	Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate ≥	483
20 breaths per minute, heart rate ≥ 90 beats per minute; with saturation of oxygen (SpO2 )	484
> 93% on room air at sea level1	
485
486
• 	No clinical signs indicative of Severe or Critical Severity	487
488
Severe COVID-19	489
490
• 	Positive testing by virologic test (i.e., a nucleic acid amplification test or an antigen test)	491
492
• 	Symptoms suggestive of severe systemic illness with COVID-19, which could include	493
any symptom of moderate illness or shortness of breath at rest, or respiratory distress	494
495
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 FDA’s Pulse Oximeter Accuracy and
Limitations: FDA Safety Communication, issued February 19, 2021, available at https://www.fda.gov/news-
events/fda-brief/fda-brief-fda-warns-about-limitations-and-accuracy-pulse-oximeters.

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• 	Clinical signs indicative of severe systemic illness with COVID-19, such as respiratory	496
rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea level or	497
PaO2 /FiO2 < 300	498
499
• 	No clinical criteria for Critical Severity	500
501
Critical COVID-19	502
503
• 	Positive testing by virologic test (i.e., a nucleic acid amplification test or an antigen test)	504
505
• 	Evidence of critical illness, defined by at least one of the following:	506
507
– 	Respiratory failure defined as requiring at least one of the following:	508
509
 	Endotracheal intubation and mechanical ventilation, oxygen delivered by high-	510
flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal	511
cannula at flow rates > 20 L/min with fraction of delivered oxygen ≥ 0.5),	512
noninvasive positive pressure ventilation, extracorporeal membrane oxygenation	513
514
– 	Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure <	515
60 mm Hg or requiring vasopressors)	516
517
– 	Multi-organ dysfunction/failure	518
519
520

Contains Nonbinding Recommendations
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APPENDIX B	521
522
DRUG RESISTANCE ANALYSIS	523
524
The drug resistance analysis plan should include the following:	525
526
• 	Characterize the antiviral activity of the drug in cell culture assays against a panel of	527
geographically, temporally, and phylogenetically distinct SARS-CoV-2 isolates,	528
including isolates representative of the most common variants currently circulating	529
globally.	530
531
• 	Evaluate combination antiviral activity relationships in cell culture assays between	532
candidate drugs planned for use in a combination regimen, or between the candidate	533
drug(s) and any other authorized or approved drugs if they are anticipated to be used in	534
combination.	535
536
• 	Select for viruses resistant to the drug in cell culture assays and characterize drug-	537
resistant viruses genotypically and phenotypically to support drug resistance and cross-	538
resistance analyses. These studies should be conducted under appropriate	539
biocontainment1 or consider using a surrogate or recombinant virus expressing the	540
SARS-CoV-2 target protein.	541
542
• 	Identify reported SARS-CoV-2 amino acid polymorphisms in the drug target and	543
describe their prevalence and rates of emergence in publicly available viral sequence	544
databases. If the drug has been co-crystalized with the viral target protein, identify	545
polymorphisms in the viral target at amino acid positions that are within 5 angstroms of	546
the drug structure.	547
548
• 	Include detailed plans in clinical protocols to (a) characterize the impact of SARS-CoV-2	549
genetic variability on clinical and virologic outcomes (i.e., baseline resistance analyses)	550
and (b) identify SARS-CoV-2 genetic changes associated with treatment (i.e., treatment-	551
emergent resistance analyses).	552
553
• 	Characterize the impact of specific amino acid variants in the drug target on drug activity	554
using cell culture phenotype assays. If a pseudotyped virus-like particle assay or other	555
surrogate assay is used, conduct validation studies showing that the surrogate assay yields	556
results that are consistent with those obtained with authentic virus regarding the relative	557
impact of different variants.	558
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 Prevention’s 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://aspr.hhs.gov/S3/Documents/USG-
Policy-for-Oversight-of-DURC-and-PEPP-May2024-508.pdf.

Contains Nonbinding Recommendations
17
559
• 	Assess the potential for cross-resistance with other drugs with the same target or similar	560
mechanism of action based on results of genotypic and phenotypic assays.	561
562
• 	Monitor continuously for emerging SARS-CoV-2 variants and evaluate phenotypically	563
any specific variants in the drug target that are becoming prevalent or could potentially	564
impact drug activity.	565
566
• 	Conduct proof of principle studies in small animal models given the limited availability	567
of nonhuman primates.	568
569
• 	Identify known human genetic polymorphisms and characterize their potential impact on	570
drug activity in nonclinical and/or clinical studies if the drug targets a host factor. The	571
types and frequencies of polymorphisms in different racial/ethnic groups should be	572
provided to FDA. Samples for resistance assessments should be collected in clinical trials	573
for host targeting antivirals as resistance can occur with these drugs.	574
575
• 	Follow established FDA guidance for submission of next generation sequencing data	576
generated from clinical trials.2 Consult with the appropriate review division for additional	577
advice on collection and submission of drug resistance data.	578
579
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.

Contains Nonbinding Recommendations
18
APPENDIX C	580
581
IMPACT OF DRUGS ON VIRAL SHEDDING AND IMMUNE RESPONSES	582
583
Clinical trial protocols should include plans to characterize the impact of drugs on viral shedding	584
and immune responses as follows:	585
586
• 	Indicate specific time points and clinical specimens to be collected and analyzed.	587
588
• 	Describe the specific types of respiratory samples to be collected (e.g., nasopharyngeal	589
swabs, nasal mid-turbinate swab, saliva) and the collection procedures.	590
591
• 	Collect and analyze the same specimen type(s) for baseline and subsequent time points	592
when assessing the impact of treatment on viral shedding as assays may have varying	593
sensitivity or performance for different respiratory specimen types.	594
595
• 	Collect nonrespiratory specimens (e.g., blood, bronchoalveolar lavage fluid) for virologic	596
analyses when feasible to assess the impact of antiviral treatment on virus replication in	597
other compartments, which may play a role in disease pathogenesis.	598
599
• 	Include an assessment of viral RNA levels (e.g., quantitative RT-PCR) for viral shedding	600
analyses. Sponsors are encouraged to assess viral RNA shedding both quantitatively (e.g.,	601
log 10 decline from baseline at a specific time point) and qualitatively (e.g., detected or not	602
detected at a specific time point). Indicate the specific viral RNA assay(s) to be used and	603
whether they have received FDA emergency use authorization or approval.	604
605
• 	Consider conducting virus infectivity assays to characterize the impact of treatment on	606
shedding of cell culture infectious virus. Such assays should be conducted under	607
appropriate biocontainment.1	
608
609
• 	Describe assay performance characteristics, including any known or predicted impact of	610
emerging SARS-CoV-2 variants on assay performance.	611
612
• 	Characterize the impact of treatments on markers of inflammation (e.g., pro-	613
inflammatory cytokines) and on the development of anti-SARS-CoV-2 immune	614
responses when possible.	615
616
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 Prevention’s and the National Institutes of Health’s 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://aspr.hhs.gov/S3/Documents/USG-Policy-for-Oversight-of-DURC-and-PEPP-May2024-508.pdf.

Contains Nonbinding Recommendations
19
• 	Consider conducting these laboratory assessments in central laboratories or include	617
internal assay references to minimize the potential introduction of variability attributable	618
to assessments being conducted in different laboratories.	619
620
621