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 
 
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) 
 
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 
2  Adolescent Subjects in Clinical Trials of Drugs and Biological 
3  Products for COVID-19 Prevention or Treatment 
4  Guidance for Industry1 
5   
6   
7   
8  This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
9  this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
10  can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
11  To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the 
12  title page.   
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  This guidance provides sponsors and investigators with considerations for approaches on how 
19  common symptoms related to the Coronavirus Disease 2019 (COVID-19) can be measured and 
20  analyzed in clinical trials evaluating drugs or biological products2 for the prevention or treatment 
21  of COVID-19 in outpatient adult and adolescent3 subjects.4  This guidance is not intended for 
22  development programs evaluating products to treat or prevent postinfectious COVID-19 
23  conditions (e.g., long COVID, multisystem inflammatory syndrome) in children and adults, or 
24  development programs for preventative vaccines.  This guidance does not address considerations 
25  for clinical trial design other than those pertaining to the measurement and analysis of COVID-
26  19-related symptoms among outpatients.  Considerations for patients with COVID-19 who 
27  require hospitalization are out of scope for this guidance. 
28   
29  FDA is implementing this guidance without prior public comment because the Agency has 
30  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 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.  
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Contains Nonbinding Recommendations 
31  and (g)(3). FDA made this determination because although the COVID-19-related public health 
32  emergency under section 319 of the Public Health Services Act has expired, SARS-CoV-2 
33  continues to circulate, COVID-19 remains a serious health risk for some individuals, and there is 
34  a need to ensure that sponsors are aware of FDAs recommendations to facilitate timely 
35  development of drugs and biological products for treatment and prevention of COVID-19.  This 
36  guidance supersedes the guidance of the same name issued on September 29, 2020.  
37   
38  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
39  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
40  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
41  the word should in Agency guidance means that something is suggested or recommended, but 
42  not required. 
43   
44   
45  II.  BACKGROUND 
46   
47  Sponsors continue to conduct outpatient prevention or treatment clinical trials in adult and 
48  adolescent subjects that incorporate assessments of COVID-19-related symptoms; however, 
49  challenges persist.  These challenges include but are not limited to the identification of methods 
50  to assess the numerous and heterogenous symptoms across subjects, patient burden, poor 
51  compliance with diary completion, and potential missing data.  To address these challenges, 
52  sponsors should identify key common symptoms for daily assessments based on the program-
53  specific context of use (e.g., target population, mechanism of action of the investigational 
54  product, underlying pathophysiology of COVID-19, symptomatology associated with the 
55  currently circulating variants) to optimize the measurement strategy for symptoms most likely to 
56  change while lessening the burden on trial subjects.5  To assist sponsors, this guidance provides 
57  an exemplary set of common COVID-19-related symptoms as well as an approach to their 
58  measurement for use in clinical trials (see Table 1).  The symptom items are derived from 
59  existing literature, the Centers for Disease Control and Prevention (CDC),6 and clinical research.   
60   
61   
 
5 See the FDA Patient-Focused Drug Development (PFDD) Guidance Series for Enhancing the Incorporation of the 
Patients 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 FDAs 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 CDCs 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. 
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Contains Nonbinding Recommendations 
62  III.  DISCUSSION 
63   
64  A.  General Recommendations 
65   
66  FDA recommends the following for sponsors initiating clinical trials evaluating drugs for the 
67  prevention or treatment of COVID-19 in outpatient adult and adolescent subjects: 
68   
69    Use patient-reported outcome (PRO) instruments7 to assess COVID-19-related 
70  symptoms; the use of PRO instruments is advised when measuring signs and symptoms best 
71  known by the patient or best measured from the patient perspective.   
72   
73    Consult with the appropriate FDA review division regarding PRO instruments proposed 
74  for use. 
75   
76    Conduct PRO assessments of COVID-19-related symptoms at least every 24 hours and 
77  conduct assessments at the same time each day.   
78   
79    Use electronic data collection systems with reminders to trial subjects to complete the 
80  PRO instrument to minimize missing data and provide time stamps of completion.  
81  Alternatively, if a paper-based diary is used, sponsors should send reminders (e.g., phone 
82  calls, text messages, email) to trial subjects.   
83   
84    Include a set of common COVID-19-related symptoms (for an example, see Table 1) in 
85  the daily PRO assessments of all trial subjects regardless of which symptoms a subject 
86  had at baseline, as new symptoms may appear following the baseline assessment.   
87   
88    Consider whether a comprehensive set of COVID-19-related symptoms, beyond the set 
89  of common COVID-19-related symptoms assessed in the daily PRO instrument, is useful 
90  when collected at study baseline and again at landmark time points8 and also whether a 
91  transition to weekly PRO assessments later in the study period would be useful, 
92  depending on the program-specific context of use (e.g., study duration). 
93   
 
7 See the FDA PFDD Guidance Series for Enhancing the Incorporation of the Patients 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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Contains Nonbinding Recommendations 
94    Conduct an evaluation to ensure the PRO instruments comprehensibility and usability 
95  before implementation in a trial to mitigate the risk of poor instrument performance.9,10  
96  Such an evaluation should be conducted even if the sponsor chooses to use an approach 
97  similar to the example approach shown in Table 1. 
98   
99  B.  Example Assessment of Key COVID-19-Related Symptoms 
100   
101  Given the heterogeneous nature of COVID-19-related symptoms, key COVID-19-related 
102  symptoms should be assessed systematically to provide an accurate evaluation of benefit in 
103  outpatients.  In this guidance we provide an exemplary set of 14 common COVID-19-related 
104  symptoms to consider in Table 1 (as described below).  Although we recommend assessing these 
105  items to capture change in common COVID-19-related symptoms (e.g., emergence, 
106  improvement, or worsening) during the clinical trials, a subset of key COVID-19-related 
107  symptoms can be used to derive symptom-based efficacy endpoints.  Determination of which 
108  subset to investigate will depend on what aspect(s) of the condition the study drug is expected to 
109  improve as well as symptomatology associated with the currently circulating COVID-19 
110  variant(s) of concern.  The final assessment plan should be informed by qualitative evidence 
111  from patient interviews and/or the literature. 
112   
113    In the example in Table 1, the following applies for rating each symptom: 
114   
115    Items 1 to 10, 13, and 14:  Trial subjects rate symptom severity at its worst over a 

116  specified recall period (e.g., 24 hours) using a verbal rating scale for severity.   
117   
118    Items 11 (vomiting) and 12 (diarrhea) are each recorded promptly after a vomiting or 

119  diarrhea episode occurs.  
120   
121    In the example in Table 1, there is no total score.  Each symptom is scored individually 
122  using the following response options and/or scoring values: 
123   
124    Items 1 to 10:  None = 0, Mild = 1, Moderate = 2, and Severe = 3.  

125   
126    Items 11 and 12:  Record the time of event occurrence. 

127   
128    Items 13 and 14:  Sense of smell/taste same as usual = 0, Sense of smell/taste less 

129  than usual = 1, No sense of smell/taste = 2.  
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 FDAs current thinking on this topic.   
 
4   
Contains Nonbinding Recommendations 
132  Table 1.  Example Assessment of 14 Common COVID-19-Related Symptoms:  Sample of 
133  Items and Response Options  
134   
 
Example of items 
Example of response 
 
options 
For items 110, sample item wording could be What 
and scoring* 
was the severity of your [insert symptom] at its worst 
 
over the past 24 hours? 
 
1.  Stuffy or runny nose 
2.  Sore throat 
3.  Shortness of breath (difficulty breathing) 
None = 0  
4.  Cough 
 
Mild = 1  
5.  Low energy or tiredness   
Moderate = 2  
6.  Muscle or body aches   
Severe = 3 
7.  Headache 
8.  Chills or shivering 
9.  Feeling hot or feverish 
10.  Nausea (feeling like you wanted to throw up) 
Record each episode of 
11. If you had vomiting (throwing up)**   
vomiting  
5   
Contains Nonbinding Recommendations 
 
Example of items 
Example of response 
 
options 
For items 110, sample item wording could be What 
and scoring* 
was the severity of your [insert symptom] at its worst 
 
over the past 24 hours? 
 
Record each episode of 
12. If you had diarrhea (loose or watery stools) **   
diarrhea 
 
My sense of smell is THE 
SAME AS usual = 0  
 
13.  Rate your sense of smell in the past 24 hours  My sense of smell is LESS 
THAN usual = 1  
 
I have NO sense of smell = 2 
 
 
My sense of taste is THE 
SAME AS usual = 0  
 
14. Rate your sense of taste in the past 24 hours  My sense of taste is LESS 
THAN usual = 1  
 
I have NO sense of taste = 2 
 
135  * Note:  Score values are included in the table for ease of reference.  FDA cautions against including the score 
136  values within the verbal rating scale response options presented to trial subjects because these values may distract 
137  subjects with unnecessary information.  
138  ** The statements shown for items 11 and 12 are intended for documentation in real-time.  For frequent events or 
139  episodes, the sponsor should consider an event-driven electronic diary rather than a diary completed once daily with 
140  a 24-hour recall.11  
141   In lieu of items 13 and 14, sponsors may include optional questions on severity of loss and/or alteration of 
142  smell/taste based on the program-specific context of use.  The item descriptions should include sufficient detail for 
143  the respondent to understand the concept being asked (e.g., loss of smell versus parosmia and/or phantosmia-like 
144  alteration of smell).  The same recommendation applies to item 14.  Understandability of the response options 
145  should be supported by qualitative evidence from patient interviews and/or the literature.  
146   
147    Sponsors can consider using alternative items and response options for assessment of 
148  common COVID-19-related symptoms.  For example, a sponsor can consider using a 4-
149  point (none/mild/moderate/severe) or binary response (yes/no) scale for assessment of 
150  patient-reported loss and/or alteration of smell and taste; vomiting and diarrhea might 
151  also be rated on a verbal rating frequency scale with a 24-hour recall period. 
 
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 FDAs current thinking on this topic.  
6   
Contains Nonbinding Recommendations 
152   
153    According to the mechanism of action of the investigational product and the underlying 
154  pathophysiology of COVID-19, clinical manifestations of the currently circulating 
155  COVID-19 variant(s) of concern, and program-specific study design, sponsors can also 
156  assess additional emerging symptoms (e.g., cognitive dysfunction) if appropriate. 
157   
158  When designing and implementing PRO instruments, sponsors should consider the following 
159  recommendations: 
160   
161    FDA recommends using response scales that include verbal descriptors (e.g., none, mild, 
162  moderate, severe) because the absence of verbal descriptors may create difficulty in 
163  interpretation.  Accordingly, response scales such as visual analog scales and 0-to-10 
164  numeric rating scales are not directly interpretable and may result in interpretation 
165  difficulties in this context. 
166   
167    FDA recommends avoiding an excessively large number of items in the PRO 
168  instrument(s), which may lead to unnecessary patient burden, poor compliance with diary 
169  completion, and missing data. 
170   
171  C.  Considerations for Outpatient Clinical Trial Endpoint Selection 
172   
173  1.  Endpoint Selection 
174   
175  Sponsors should consider the following: 
176   
177    The selection of time point(s) for clinical endpoint assessments in prevention or treatment 
178  trials in outpatient adult and adolescent subjects is dependent on up-to-date knowledge of 
179  the time course of COVID-19-related symptom onset or resolution.  For example, clinical 
180  findings show that certain symptoms (e.g., cough, fatigue, or alterations in taste and 
181  smell) may take longer to resolve in comparison to other symptoms.12,13  Furthermore, 
182  the CDC has reported findings of COVID-19 rebound, which may be part of the natural 
183  history of SARS-CoV-2 infection in some individuals.  The rebound included a 
184  recurrence of COVID-19 symptoms, but the severity of the illness was mild.14 
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):335344. 
 
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):729732. 
 
14 See the CDC Health Alert Networks Covid 19 Rebound After Paxlovid Treatment, available at 
https://emergency.cdc.gov/han/2022/pdf/CDC_HAN_467.pdf.  
 
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Contains Nonbinding Recommendations 
186    Sponsors can use early phase trials in the target patient population to examine the effect 
187  of an investigational drug on the time course of symptoms to inform endpoint 
188  development for pivotal trials.  Sponsors can consider a variety of endpoint definitions to 
189  evaluate the effect of a drug on common COVID-19-related symptoms.   
190   
191    FDA encourages sponsors to provide a rationale to support their proposed endpoints, 
192  taking into account relevant information from literature sources and any relevant clinical 
193  trials. 
194   
195  2.  Trials of Drugs for Treatment of COVID-19 
196   
197  Sponsors should consider the following: 
198   
199    As described in the guidance for industry COVID-19:  Developing Drugs and Biological 
200  Products for Treatment or Prevention, an appropriate endpoint could be the time to 
201  sustained symptom alleviation or resolution assessed over an appropriate duration.   
202   
203    Sustained symptom alleviation or resolution can be defined as occurring when no key 
204  COVID-19-related symptom scored higher than a prespecified threshold over a clinically 
205  meaningful time period (as documented using a PRO instrument).   
206   
207    To evaluate clinical benefit, sponsors should include trial entry criteria defining the 
208  minimal baseline severity score for COVID-19-related symptoms (e.g., at least two 
209  symptoms with a score of 2 or higher using the scoring system shown in Table 115).  
210   
211  FDA does not recommend the following: 
212   
213    Defining endpoints based on adding scores of the items within a set of common COVID-
214  19-related symptoms to form an aggregate score.  Given the heterogeneity of COVID-19-
215  related symptoms, any single trial subject may only experience a small subset of the 
216  common COVID-19-related symptoms described in this guidance. 
217   
218    Calculating an area under the curve of COVID-19-related symptoms, as this metric is not 
219  easily interpretable in this context of use.   
220   
221  3.  Trials of Drugs for Prevention of COVID-19 
222   
223  Sponsors should consider the following: 
224   
225    As described in the guidance for industry COVID-19:  Developing Drugs and Biological 
226  Products for Treatment or Prevention, there is interest in ascertaining whether the 
227  severity of COVID-19-related symptoms is milder in trial subjects receiving prophylaxis 
228  compared with subjects not receiving prophylaxis.  
 
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.  
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Contains Nonbinding Recommendations 
229   
230    Sponsors should collect data on COVID-19-related symptoms and other endpoints to 
231  characterize levels of severity for prevention trials.16  Sponsors can consider using the set 
232  of 14 common COVID-19-related symptoms, as described in Table 1, in such data 
233  collection.  
234   
235  D.  Handling Data  
236   
237  Sponsors developing drugs for the prevention or treatment of COVID-19 and investigators 
238  conducting related clinical trials should consider the following regarding missing data and other 
239  related issues for clinical trials: 
240   
241    Sponsors and investigators should make efforts to minimize the amount of missing data.  
242  These efforts should generally include providing reminders (e.g., phone calls, text 
243  messages, email) to trial subjects to complete PRO instruments, monitoring adherence 
244  with PRO instrument completion throughout the assessment period, following up with 
245  trial subjects who are not successfully completing PRO instruments (and, where 
246  permissible, close contacts if the trial subject is not responding), supplemental training of 
247  trial subjects, and recording verbal responses for those who are unable to self-record 
248  because of illness or other circumstances.  FDA recommends obtaining contact 
249  information for close contacts of trial subjects for use in case of nonresponse.  If the 
250  investigator or a member of the study team plans to contact a family member or other 
251  close contact when subjects do not respond to follow-up, this should be described in the 
252  informed consent document approved by the institutional review board.  The reasons for 
253  missing data should be documented.  We recommend employing risk-based approaches, 
254  including centralized monitoring in clinical trials, to ensure data quality and integrity.17 
255   
256    The informed consent process18 and informed consent document should include 
257  information to educate prospective subjects about the continued scientific importance of 
258  their follow-up data even if they choose to discontinue treatment. 
259   
260    The sponsor should prospectively plan appropriate methods for handling missing data in 
261  the development of endpoints and conduct of analyses, considering the reason for the 
 
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 FDAs 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.   
 
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Contains Nonbinding Recommendations 
262  missing data.19  Sensitivity analyses considering different approaches to account for the 
263  missing data should be specified in the statistical analysis plan.20 
264   
265    Sponsors should prospectively specify how intercurrent events, including hospitalization 
266  and death, will be handled in the statistical analysis. 
267   
268    The aim should be to ascertain vital status for all COVID-19 trial subjects even after a 
269  subject decides to discontinue treatment or discontinue participation in the trial, including 
270  follow-up for key outcomes, while adhering to informed consent requirements.21 
271   
272  E.  Additional COVID-19-Related Assessments 
273   
274  In addition to assessment of key COVID-19-related symptoms, such as by using the assessments 
275  provided as an example in Table 1, FDA recommends that sponsors standardize the collection 
276  and reporting of other clinical trial assessments for trial subjects.  Additional assessments and 
277  their associated methods that sponsors can consider include the following: 
278   
279    Use of any medications to treat some of the COVID-19-related symptoms (e.g., 
280  analgesics, antipyretics):  The name of medication, dose, dosage form, and date and 
281  time(s) of administration should be reported. 
282   
283    Body temperature:  The timing and the route of the body temperature assessment method 
284  (e.g., oral) should be specified in the protocol, and sponsors should provide thermometers 
285  to trial subjects. 
286   
287    Oxygen saturation:  Pulse oximetry data should be collected, and the sponsor should 
288  provide that equipment and provide training or instruction on its use to subjects. 
289   
290    Patient-reported global impression items assessing a) return to usual health, b) return to 
291  usual activities, c) overall COVID-19-related symptoms, and d) cluster of COVID-19-
292  related symptom (e.g., respiratory, digestive):  examples of patient-reported global 
293  impression item(s) can include the following: 
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 
subjects 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 subjects vital status after a subject withdraws from a 
clinical trial. 
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Contains Nonbinding Recommendations 
295    In the past 24 hours, have you returned to your usual health (before your COVID-19 

296  illness)?  Yes or No 
297   
298    In the past 24 hours, have you returned to your usual activities (before your COVID-

299  19 illness)?  Yes or No 
300   
301    In the past 24 hours, what was the severity of your overall COVID-19-related 

302  symptoms at their worst?  None, Mild, Moderate, or Severe 
303   
304    In the past 24 hours, what was the severity of your (cluster name: e.g., respiratory) 

305  COVID-19-related symptoms at their worst?  None, Mild, Moderate, or Severe 
306   
307  Further considerations include the frequency of patient-reported global impression items which 
308  may be less frequent (i.e., weekly) with differing recall periods including now, past 24 hours, or 
309  past week depending on the intent of the assessment. 
11