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 : Guidance for Industry

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

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
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) David Reasner at 301-837-7667 or email
DavidReasner@fda.hhs.gov 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)
February 2024
Clinical/Medical

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
Guidance for Industry
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Center for Drug Evaluation and Research
Food and Drug Administration
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Silver Spring, MD 20993-0002
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https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
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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)
February 2024
Clinical/Medical

Contains Nonbinding Recommendations
Table of Contents
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	DISCUSSION .................................................................................................................... 3
A. 	General Recommendations ........................................................................................................... 3
B. 	Example Assessment of Key COVID-19-Related Symptoms ..................................................... 4
C. 	Considerations for Outpatient Clinical Trial Endpoint Selection ............................................. 7
1. Endpoint Selection ........................................................................................................................... 7
2. Trials of Drugs for Treatment of COVID-19 ................................................................................... 8
3. Trials of Drugs for Prevention of COVID-19 .................................................................................. 8
D. 	Handling Data ................................................................................................................................ 9
E. 	Additional COVID-19-Related Assessments ............................................................................. 10

Contains Nonbinding Recommendations
1
Assessing COVID-19-Related Symptoms in Outpatient Adult and	1
Adolescent Subjects in Clinical Trials of Drugs and Biological	2
Products for COVID-19 Prevention or Treatment	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 staff responsible for this guidance as listed on the	11
title page.	12
13
14
15
I. 	INTRODUCTION	16
17
This guidance provides sponsors and investigators with considerations for approaches on how	18
common symptoms related to the Coronavirus Disease 2019 (COVID-19) can be measured and	19
analyzed in clinical trials evaluating drugs or biological products2 for the prevention or treatment	20
of COVID-19 in outpatient adult and adolescent3 subjects.4 This guidance is not intended for	21
development programs evaluating products to treat or prevent postinfectious COVID-19	22
conditions (e.g., long COVID, multisystem inflammatory syndrome) in children and adults, or	23
development programs for preventative vaccines. This guidance does not address considerations	24
for clinical trial design other than those pertaining to the measurement and analysis of COVID-	25
19-related symptoms among outpatients. Considerations for patients with COVID-19 who	26
require hospitalization are out of scope for this guidance.	27
28
FDA is implementing this guidance without prior public comment because the Agency has	29
determined that prior public participation is not feasible or appropriate (see 21 CFR 10.115(g)(2)	30
1 This guidance has been prepared by the Office of New Drugs in the Center for Drug Evaluation and Research in
cooperation with the Center for Biologics Evaluation and Research 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 For the purposes of this guidance, adolescents are defined as 12 years of age to younger than 18 years of age.
4 For treatment trials, sponsors should document diagnosis of laboratory-confirmed SARS-CoV-2, as well as the
duration of symptoms before treatment. Sponsors of clinical trials to evaluate drugs and biological products to treat
or prevent COVID-19 should see the guidance for industry, investigators, and institutional review boards
Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions Due To Disasters
and Public Health Emergencies (September 2023) and the guidance for industry COVID-19: Developing Drugs and
Biological Products for Treatment or Prevention (November 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.

Contains Nonbinding Recommendations
2
and (g)(3). FDA made this determination because although the COVID-19-related public health	31
emergency under section 319 of the Public Health Services Act has expired, SARS-CoV-2	32
continues to circulate, COVID-19 remains a serious health risk for some individuals, and there is	33
a need to ensure that sponsors are aware of FDA’s recommendations to facilitate timely	34
development of drugs and biological products for treatment and prevention of COVID-19. This	35
guidance supersedes the guidance of the same name issued on September 29, 2020.	36
37
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	38
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	39
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	40
the word should in Agency guidance means that something is suggested or recommended, but	41
not required.	42
43
44
II. 	BACKGROUND	45
46
Sponsors continue to conduct outpatient prevention or treatment clinical trials in adult and	47
adolescent subjects that incorporate assessments of COVID-19-related symptoms; however,	48
challenges persist. These challenges include but are not limited to the identification of methods	49
to assess the numerous and heterogenous symptoms across subjects, patient burden, poor	50
compliance with diary completion, and potential missing data. To address these challenges,	51
sponsors should identify key common symptoms for daily assessments based on the program-	52
specific context of use (e.g., target population, mechanism of action of the investigational	53
product, underlying pathophysiology of COVID-19, symptomatology associated with the	54
currently circulating variants) to optimize the measurement strategy for symptoms most likely to	55
change while lessening the burden on trial subjects.5 To assist sponsors, this guidance provides	56
an exemplary set of common COVID-19-related symptoms as well as an approach to their	57
measurement for use in clinical trials (see Table 1). The symptom items are derived from	58
existing literature, the Centers for Disease Control and Prevention (CDC),6 and clinical research.	59
60
61
5 See the FDA Patient-Focused Drug Development (PFDD) Guidance Series for Enhancing the Incorporation of the
Patient’s Voice in Medical Product Development and Regulatory Decision Making, available at
https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-
series-enhancing-incorporation-patients-voice-medical. The guidance series is part of FDA’s PFDD efforts in
accordance with the 21st Century Cures Act and the Food and Drug Administration Reauthorization Act of 2017
Title I. 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. When final, the PFDD
guidance series will replace the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product
Development to Support Labeling Claims (December 2009).
6 For detailed information, see the CDC’s COVID-19 Symptoms of Coronavirus web page, available at
https://www.cdc.gov/coronavirus/2019-ncov/symptoms-
testing/symptoms.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-
ncov%2Fabout%2Fsymptoms.html.

Contains Nonbinding Recommendations
3
III. 	DISCUSSION	62
63
A. 	General Recommendations	64
65
FDA recommends the following for sponsors initiating clinical trials evaluating drugs for the	66
prevention or treatment of COVID-19 in outpatient adult and adolescent subjects:	67
68
• 	Use patient-reported outcome (PRO) instruments7 to assess COVID-19-related	69
symptoms; the use of PRO instruments is advised when measuring signs and symptoms best	70
known by the patient or best measured from the patient perspective .	71
72
• 	Consult with the appropriate FDA review division regarding PRO instruments proposed	73
for use.	74
75
• 	Conduct PRO assessments of COVID-19-related symptoms at least every 24 hours and	76
conduct assessments at the same time each day.	77
78
• 	Use electronic data collection systems with reminders to trial subjects to complete the	79
PRO instrument to minimize missing data and provide time stamps of completion.	80
Alternatively, if a paper-based diary is used, sponsors should send reminders (e.g., phone	81
calls, text messages, email) to trial subjects.	82
83
• 	Include a set of common COVID-19-related symptoms (for an example, see Table 1) in	84
the daily PRO assessments of all trial subjects regardless of which symptoms a subject	85
had at baseline, as new symptoms may appear following the baseline assessment.	86
87
• 	Consider whether a comprehensive set of COVID-19-related symptoms, beyond the set	88
of common COVID-19-related symptoms assessed in the daily PRO instrument, is useful	89
when collected at study baseline and again at landmark time points8 and also whether a	90
transition to weekly PRO assessments later in the study period would be useful,	91
depending on the program-specific context of use (e.g., study duration).	92
93
7 See the FDA PFDD Guidance Series for Enhancing the Incorporation of the Patient’s Voice in Medical Product
Development and Regulatory Decision Making, available at https://www.fda.gov/drugs/development-approval-
process-drugs/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-
medical.
8 Landmark times are predefined fixed time points after baseline.

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• 	Conduct an evaluation to ensure the PRO instrument’s comprehensibility and usability	94
before implementation in a trial to mitigate the risk of poor instrument performance.9,10	
95
Such an evaluation should be conducted even if the sponsor chooses to use an approach	96
similar to the example approach shown in Table 1.	97
98
B. 	Example Assessment of Key COVID-19-Related Symptoms	99
100
Given the heterogeneous nature of COVID-19-related symptoms, key COVID-19-related	101
symptoms should be assessed systematically to provide an accurate evaluation of benefit in	102
outpatients. In this guidance we provide an exemplary set of 14 common COVID-19-related	103
symptoms to consider in Table 1 (as described below). Although we recommend assessing these	104
items to capture change in common COVID-19-related symptoms (e.g., emergence,	105
improvement, or worsening) during the clinical trials, a subset of key COVID-19-related	106
symptoms can be used to derive symptom-based efficacy endpoints. Determination of which	107
subset to investigate will depend on what aspect(s) of the condition the study drug is expected to	108
improve as well as symptomatology associated with the currently circulating COVID-19	109
variant(s) of concern. The final assessment plan should be informed by qualitative evidence	110
from patient interviews and/or the literature.	111
112
• 	In the example in Table 1, the following applies for rating each symptom:	113
114
– 	Items 1 to 10, 13, and 14: Trial subjects rate symptom severity at its worst over a	115
specified recall period (e.g., 24 hours) using a verbal rating scale for severity.	116
117
– 	Items 11 (vomiting) and 12 (diarrhea) are each recorded promptly after a vomiting or	118
diarrhea episode occurs.	119
120
• 	In the example in Table 1, there is no total score. Each symptom is scored individually	121
using the following response options and/or scoring values:	122
123
– 	Items 1 to 10: None = 0, Mild = 1, Moderate = 2, and Severe = 3.	124
125
– 	Items 11 and 12: Record the time of event occurrence.	126
127
– 	Items 13 and 14: Sense of smell/taste same as usual = 0, Sense of smell/taste less	128
than usual = 1, No sense of smell/taste = 2.	129
130
131
9 See the guidance for industry, Food and Drug Administration staff, and other stakeholders Patient-Focused Drug
Development: Methods to Identify What Is Important to Patients (February 2022).
10 See the draft guidance for industry, Food and Drug Administration staff, and other stakeholders Patient-Focused
Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments (June
2022). When final, this guidance will represent the FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
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Table 1. Example Assessment of 14 Common COVID-19-Related Symptoms: Sample of	132
Items and Response Options	133
134
Example of items
For items 1–10, sample item wording could be “What
was the severity of your [insert symptom] at its worst
over the past 24 hours?”
Example of response
options
and scoring*
1. 	Stuffy or runny nose
None = 0
Mild = 1
Moderate = 2
Severe = 3
2. 	Sore throat
3. 	Shortness of breath (difficulty breathing)
4. 	Cough
5. 	Low energy or tiredness
6. 	Muscle or body aches
7. 	Headache
8. 	Chills or shivering
9. 	Feeling hot or feverish
10. 	Nausea (feeling like you wanted to throw up)
11. If you had vomiting (throwing up) ** 	Record each episode of
vomiting

Contains Nonbinding Recommendations
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Example of items
For items 1–10, sample item wording could be “What
was the severity of your [insert symptom] at its worst
over the past 24 hours?”
Example of response
options
and scoring*
12. If you had diarrhea (loose or watery stools) ** 	Record each episode of
diarrhea
13. 	Rate your sense of smell in the past 24 hours†
My sense of smell is THE
SAME AS usual = 0
My sense of smell is LESS
THAN usual = 1
I have NO sense of smell = 2
14. Rate your sense of taste in the past 24 hours†
My sense of taste is THE
SAME AS usual = 0
My sense of taste is LESS
THAN usual = 1
I have NO sense of taste = 2
* Note: Score values are included in the table for ease of reference. FDA cautions against including the score	135 values within the verbal rating scale response options presented to trial subjects because these values may distract	136 subjects with unnecessary information.	137 ** The statements shown for items 11 and 12 are intended for documentation in real-time. For frequent events or	138 episodes, the sponsor should consider an event-driven electronic diary rather than a diary completed once daily with	139 a 24-hour recall.11	
140 † In lieu of items 13 and 14, sponsors may include optional questions on severity of loss and/or alteration of	141 smell/taste based on the program-specific context of use. The item descriptions should include sufficient detail for	142 the respondent to understand the concept being asked (e.g., loss of smell versus parosmia and/or phantosmia-like	143 alteration of smell). The same recommendation applies to item 14. Understandability of the response options	144 should be supported by qualitative evidence from patient interviews and/or the literature.	145
146
• 	Sponsors can consider using alternative items and response options for assessment of	147
common COVID-19-related symptoms. For example, a sponsor can consider using a 4-	148
point (none/mild/moderate/severe) or binary response (yes/no) scale for assessment of	149
patient-reported loss and/or alteration of smell and taste; vomiting and diarrhea might	150
also be rated on a verbal rating frequency scale with a 24-hour recall period.	151
11 See the draft guidance for industry, Food and Drug Administration staff, and other stakeholders Patient-Focused
Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints For Regulatory Decision-Making
(April 2023). When final, this guidance will represent the FDA’s current thinking on this topic.

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152
• 	According to the mechanism of action of the investigational product and the underlying	153
pathophysiology of COVID-19, clinical manifestations of the currently circulating	154
COVID-19 variant(s) of concern, and program-specific study design, sponsors can also	155
assess additional emerging symptoms (e.g., cognitive dysfunction) if appropriate.	156
157
When designing and implementing PRO instruments, sponsors should consider the following	158
recommendations:	159
160
• 	FDA recommends using response scales that include verbal descriptors (e.g., none, mild,	161
moderate, severe) because the absence of verbal descriptors may create difficulty in	162
interpretation. Accordingly, response scales such as visual analog scales and 0-to-10	163
numeric rating scales are not directly interpretable and may result in interpretation	164
difficulties in this context.	165
166
• 	FDA recommends avoiding an excessively large number of items in the PRO	167
instrument(s), which may lead to unnecessary patient burden, poor compliance with diary	168
completion, and missing data.	169
170
C. 	Considerations for Outpatient Clinical Trial Endpoint Selection	171
172
1. 	Endpoint Selection	173
174
Sponsors should consider the following:	175
176
• 	The selection of time point(s) for clinical endpoint assessments in prevention or treatment	177
trials in outpatient adult and adolescent subjects is dependent on up-to-date knowledge of	178
the time course of COVID-19-related symptom onset or resolution. For example, clinical	179
findings show that certain symptoms (e.g., cough, fatigue, or alterations in taste and	180
smell) may take longer to resolve in comparison to other symptoms.12,13 Furthermore,	181
the CDC has reported findings of COVID-19 rebound, which may be part of the natural	182
history of SARS-CoV-2 infection in some individuals. The rebound included a	183
recurrence of COVID-19 symptoms, but the severity of the illness was mild.14	
184
185
12 Lechien JR, Chiesa-Estomba CM, Place S, Van Laethem Y, Cabaraux P, Mat Q, Huet K, Plzak J, Horoi M, Hans
S, Barillari MR, Cammaroto G, Fakhry N, Martiny D, Ayad T, Jouffe L, Hopkins C, and Saussez S, 2020, Clinical
and Epidemiological Characteristics of 1420 European Patients With Mild-to-Moderate Coronavirus Disease 2019, J
Intern Med, 288(3):335–344.
13 Boscolo-Rizzo P, Borsetto D, Fabbris C, Spinato G, Frezza D, Menegaldo A, Mularoni F, Gaudioso P, Cazzador
D, Marciani S, Frasconi S, Ferraro M, Berro C, Varago C, Micolai P, Tirelli G, Da Mosto MC, Obholzer R, Rigoli
R, Polesel J, and Hopkins C, 2020, Evolution of Altered Sense of Smell or Taste in Patients With Mildly
Symptomatic COVID-19, JAMA Otolaryngol Head Neck Surg, 146(8):729–732.
14 See the CDC Health Alert Network’s Covid 19 Rebound After Paxlovid Treatment, available at
https://emergency.cdc.gov/han/2022/pdf/CDC_HAN_467.pdf.

Contains Nonbinding Recommendations
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• 	Sponsors can use early phase trials in the target patient population to examine the effect	186
of an investigational drug on the time course of symptoms to inform endpoint	187
development for pivotal trials. Sponsors can consider a variety of endpoint definitions to	188
evaluate the effect of a drug on common COVID-19-related symptoms.	189
190
• 	FDA encourages sponsors to provide a rationale to support their proposed endpoints,	191
taking into account relevant information from literature sources and any relevant clinical	192
trials.	193
194
2. 	Trials of Drugs for Treatment of COVID-19	195
196
Sponsors should consider the following:	197
198
• 	As described in the guidance for industry COVID-19: Developing Drugs and Biological	199
Products for Treatment or Prevention, an appropriate endpoint could be the time to	200
sustained symptom alleviation or resolution assessed over an appropriate duration.	201
202
• 	Sustained symptom alleviation or resolution can be defined as occurring when no key	203
COVID-19-related symptom scored higher than a prespecified threshold over a clinically	204
meaningful time period (as documented using a PRO instrument).	205
206
• 	To evaluate clinical benefit, sponsors should include trial entry criteria defining the	207
minimal baseline severity score for COVID-19-related symptoms (e.g., at least two	208
symptoms with a score of 2 or higher using the scoring system shown in Table 115).	209
210
FDA does not recommend the following:	211
212
• 	Defining endpoints based on adding scores of the items within a set of common COVID-	213
19-related symptoms to form an aggregate score. Given the heterogeneity of COVID-19-	214
related symptoms, any single trial subject may only experience a small subset of the	215
common COVID-19-related symptoms described in this guidance.	216
217
• 	Calculating an area under the curve of COVID-19-related symptoms, as this metric is not	218
easily interpretable in this context of use.	219
220
3. 	Trials of Drugs for Prevention of COVID-19	221
222
Sponsors should consider the following:	223
224
• 	As described in the guidance for industry COVID-19: Developing Drugs and Biological	225
Products for Treatment or Prevention, there is interest in ascertaining whether the	226
severity of COVID-19-related symptoms is milder in trial subjects receiving prophylaxis	227
compared with subjects not receiving prophylaxis.	228
15 Note that the example relates to the items using verbal rating scale. For event-driven symptoms, consider a
baseline threshold frequency to reflect moderate to severe severity in the target patient population.

Contains Nonbinding Recommendations
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229
• 	Sponsors should collect data on COVID-19-related symptoms and other endpoints to	230
characterize levels of severity for prevention trials.16 Sponsors can consider using the set	231
of 14 common COVID-19-related symptoms, as described in Table 1, in such data	232
collection.	233
234
D. 	Handling Data	235
236
Sponsors developing drugs for the prevention or treatment of COVID-19 and investigators	237
conducting related clinical trials should consider the following regarding missing data and other	238
related issues for clinical trials:	239
240
• 	Sponsors and investigators should make efforts to minimize the amount of missing data.	241
These efforts should generally include providing reminders (e.g., phone calls, text	242
messages, email) to trial subjects to complete PRO instruments, monitoring adherence	243
with PRO instrument completion throughout the assessment period, following up with	244
trial subjects who are not successfully completing PRO instruments (and, where	245
permissible, close contacts if the trial subject is not responding), supplemental training of	246
trial subjects, and recording verbal responses for those who are unable to self-record	247
because of illness or other circumstances. FDA recommends obtaining contact	248
information for close contacts of trial subjects for use in case of nonresponse. If the	249
investigator or a member of the study team plans to contact a family member or other	250
close contact when subjects do not respond to follow-up, this should be described in the	251
informed consent document approved by the institutional review board. The reasons for	252
missing data should be documented. We recommend employing risk-based approaches,	253
including centralized monitoring in clinical trials, to ensure data quality and integrity.17	
254
255
• 	The informed consent process18 and informed consent document should include	256
information to educate prospective subjects about the continued scientific importance of	257
their follow-up data even if they choose to discontinue treatment.	258
259
• 	The sponsor should prospectively plan appropriate methods for handling missing data in	260
the development of endpoints and conduct of analyses, considering the reason for the	261
16 See the guidance for industry COVID-19: Developing Drugs and Biological Products for Treatment or
Prevention.
17 For additional information, see the guidance for industry A Risk-Based Approach to Monitoring of Clinical
Investigations: Questions and Answers (April 2023).
18 For information about the informed consent process, see FDA’s proposed recommendations in the guidance for
IRBs, clinical investigators, and sponsors Informed Consent (August 2023). For information about use of electronic
systems and processes that may employ multiple electronic media to obtain informed consent, see the guidance for
institutional review boards, investigators, and sponsors Use of Electronic Informed Consent: Questions and
Answers (December 2016). See also the guidance for industry, investigators, and institutional review boards
Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions Due To Disasters
and Public Health Emergencies, and the guidance for industry COVID-19: Developing Drugs and Biological
Products for Treatment or Prevention.

Contains Nonbinding Recommendations
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missing data.19 Sensitivity analyses considering different approaches to account for the	262
missing data should be specified in the statistical analysis plan.20	
263
264
• 	Sponsors should prospectively specify how intercurrent events, including hospitalization	265
and death, will be handled in the statistical analysis.	266
267
• 	The aim should be to ascertain vital status for all COVID-19 trial subjects even after a	268
subject decides to discontinue treatment or discontinue participation in the trial, including	269
follow-up for key outcomes, while adhering to informed consent requirements.21	
270
271
E. 	Additional COVID-19-Related Assessments	272
273
In addition to assessment of key COVID-19-related symptoms, such as by using the assessments	274
provided as an example in Table 1, FDA recommends that sponsors standardize the collection	275
and reporting of other clinical trial assessments for trial subjects. Additional assessments and	276
their associated methods that sponsors can consider include the following:	277
278
• 	Use of any medications to treat some of the COVID-19-related symptoms (e.g.,	279
analgesics, antipyretics): The name of medication, dose, dosage form, and date and	280
time(s) of administration should be reported.	281
282
• 	Body temperature: The timing and the route of the body temperature assessment method	283
(e.g., oral) should be specified in the protocol, and sponsors should provide thermometers	284
to trial subjects.	285
286
• 	Oxygen saturation: Pulse oximetry data should be collected, and the sponsor should	287
provide that equipment and provide training or instruction on its use to subjects.	288
289
• 	Patient-reported global impression items assessing a) return to usual health, b) return to	290
usual activities, c) overall COVID-19-related symptoms, and d) cluster of COVID-19-	291
related symptom (e.g., respiratory, digestive): examples of patient-reported global	292
impression item(s) can include the following:	293
294
19 For additional information, see the draft guidance for industry, Food and Drug Administration staff, and other
stakeholders Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for
Regulatory Decision-Making.
20 For additional information on sensitivity analysis, see the ICH guidance for industry E9(R1) Statistical Principles
for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials (May 2021).
21 For example, if a subject withdraws from the interventional portion of a clinical investigation and does not
consent to continued follow-up of associated clinical outcome information, the investigator must not access the
subject’s medical record or other confidential records that would require additional consent from the subject to
obtain the continued follow-up information (21 CFR 50.20 and 50.25(a)(1)). However, an investigator may consult
publicly available sources of information to determine a subject’s vital status after a subject withdraws from a
clinical trial.

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– 	In the past 24 hours, have you returned to your usual health (before your COVID-19	295
illness)? Yes or No	296
297
– 	In the past 24 hours, have you returned to your usual activities (before your COVID-	298
19 illness)? Yes or No	299
300
– 	In the past 24 hours, what was the severity of your overall COVID-19-related	301
symptoms at their worst? None, Mild, Moderate, or Severe	302
303
– 	In the past 24 hours, what was the severity of your (cluster name: e.g., respiratory)	304
COVID-19-related symptoms at their worst? None, Mild, Moderate, or Severe	305
306
Further considerations include the frequency of patient-reported global impression items which	307
may be less frequent (i.e., weekly) with differing recall periods including now, past 24 hours, or	308
past week depending on the intent of the assessment.	309