Revised guidance on Covid-19 symptom assessment incorporates new knowledge, adds flexibility

Background: FDA’s Covid-19-related guidance in a post-pandemic era

• The COVID-19 Public Health Emergency (PHE) was activated on January 31, 2020. Over the course of the PHE—which spanned more than three years—the FDA used its expanded authority extensively to issue new direct-to-final guidance documents, creating over 80 in total. The FDA also implemented new flexibilities for certain regulated products and processes, typically via enforcement discretion. These guidances contained language stating they were in force “for the duration of the public health emergency” – and “only for the duration of the public health emergency related to COVID-19” – including any renewals. This is according to section 319 of the Public Health Services (PHS) Act, the statutory authority under which the guidance documents were issued.
• In January 2023, the White House announced that the federal Covid-19 national emergency and PHE would officially end on May 11, 2023. In its statement of administrative policy, the White House explained that it would extend the PHE, as well as the national emergency, one more time in order to “end both emergencies” together on May 11. Following this announcement, the FDA developed a transition plan that explained what would happen to its extensive catalogue of PHE-related guidance documents, 60 of which were related to life sciences policy.
• The FDA developed four tracks for its PHE-related guidance documents: 1) Immediately expire (“no longer be in effect when the PHE declaration expires”); 2) Be revised to remain in effect for 180 days following the expiration of the PHE declaration and then expire (to allow for “an orderly transition”); 3) Be revised to continue to remain in effect for 180 days following the expiration of the PHE declaration, with further revisions during that 180-day period; 4) Not be revised and remain in effect because they are not tied to the expiration of the PHE declaration.
• On November 7, 2023, the FDA’s 180-day transition period ended, with the agency addressing all guidances in some form prior to the deadline. However, instead of actually revising all of the guidance documents slated for revision, the FDA announced that five of these guidances would remain in effect for an extended duration, with four of them to expire on March 7, 2024, and one to remain in effect until August 7, 2024. [Read Agency IQ’s complete breakdown of the FDA’s PHE guidance documents here.]
• Since then, the FDA has updated four of the five documents that received an extension. In late November, the agency published an update to its guidance on developing drugs and biologics for the treatment and prevention of Covid-19. In December, it published an update to its guidance on developing monoclonal antibody products for Covid-19 and published a master protocols guidance that replaced the Covid-19-specific guidance on the topic. And just this week, the FDA updated its guidance on symptom assessment in outpatient trials of Covid-19 products.

FDA’s guidance on assessing symptoms in outpatient clinical trials of Covid-19 products

• In September 2020, the FDA issued a guidance document (immediately in effect) on evaluating symptoms in outpatient clinical trials for products intended to prevent or treat Covid-19. When it was first published, the guidance presented an example of a symptom assessment, offered considerations for outpatient clinical trial endpoint selection and data handling, and suggested additional COVID-19-related assessments. However, the document’s utility was limited by the available knowledge at the time of its issuance. As a result, it was caveated with a disclaimer that its recommendations were developed based on the latest information provided by the Centers for Disease Control and Prevention (CDC) as of August 2020, and that the field’s knowledge regarding Covid-19-related symptom onset and resolution was “still evolving.” [ See AgencyIQ’s analysis of that guidance here.]
• This week, the FDA published an immediately-in-effect revision to this guidance. Unlike many of the agency’s other Covid-19 guidances, this document has not been revised since it was first issued almost four years ago. From a big picture standpoint, the changes to the guidance reflect the significant gains in knowledge that have occurred since its initial publication, as well as some of the pitfalls that sponsors ran into during the development of products to treat and prevent SARS-CoV-2 viral infections.
• As before, the purpose of the guidance is to discuss approaches to the measurement and analysis of “common symptoms related to the Coronavirus Disease 2019 (COVID-19).” In general, the structure and organization of the document is unchanged, with the majority of its contents dedicated to the discussion of common Covid-19 symptoms, recommendations on tools to assess these symptoms, considerations for measuring magnitude of symptoms, and a high-level discussion of how the data should be handled for eventual use in regulatory submissions.
• Like the original guidance, the scope of the revised version is focused on a specific sub-population: adolescents and adults in the outpatient (non-hospitalized) setting. As defined in the guidance, “adolescent and adult subjects” refers to those 12 years of age and older. And although the guidance covers both treatment and prevention, it is intended to be used only for near-term prevention or the treatment of a current Covid-19 infection. This latter point is clarified in a new footnote which states that “For treatment trials, sponsors should document diagnosis of laboratory-confirmed SARS-CoV-2, as well as the duration of symptoms before treatment.” As before, the guidance excludes development programs for preventative vaccines and products to treat or prevent postinfectious Covid-19 conditions, such as multisystem inflammatory syndrome and (added with this revision) long Covid-19.
• The guidance has been re-framed to align with the shift from an active pandemic to the post-pandemic world. Instead of the previous explanation that the FDA is issuing this advice to sponsors in the midst of a “national emergency” caused by a “current outbreak of respiratory disease caused by a novel coronavirus,” the background section states that this guidance has been reissued in a setting where “Sponsors continue to conduct outpatient prevention or treatment clinical trials in adult and adolescent subjects that incorporate assessments of COVID-19-related symptoms; however, challenges persist.” The revised document now provides insight on these challenges, including “the identification of methods to assess the numerous and heterogenous symptoms across subjects, patient burden, poor compliance with diary completion, and potential missing data.”
• The FDA has built additional flexibility into the guidance, acknowledging both the changing nature of Covid-19 and the array of potential treatment options. The updated guidance now states that symptoms selected by sponsors for use in clinical trials should accurately reflect the “program-specific context of use (e.g., target population, mechanism of action of the investigational product, underlying pathophysiology of COVID-19, symptomatology associated with the currently circulating variants) to optimize the measurement strategy for symptoms most likely to change while lessening the burden on trial subjects.” This is reiterated later on in the guidance, where the FDA states that “a subset of key COVID-19-related symptoms can be used to derive symptom-based efficacy endpoints. Determination of which subset to investigate will depend on what aspect(s) of the condition the study drug is expected to improve as well as symptomatology associated with the currently circulating COVID-19 variant(s) of concern.”
• While the original guidance emphasized limiting the number of symptoms assessed to reduce patient burden, the revised guidance has added some in. Under General Recommendations, which centers around the use of patient-reported outcome (PRO) instruments, a new bullet point advises sponsors to “Consider whether a comprehensive set of COVID-19-related symptoms, beyond the set of common COVID-19-related symptoms assessed in the daily PRO instrument, is useful when collected at study baseline and again at landmark time points and also whether a transition to weekly PRO assessments later in the study period would be useful, depending on the program-specific context of use (e.g., study duration).”
• In line with increased flexibility, the guidance now notes that sponsors may include “optional questions on severity of loss and/or alteration of smell/taste based on the program-specific context of use. The item descriptions should include sufficient detail for the respondent to understand the concept being asked (e.g., loss of smell versus parosmia and/or phantosmia-like alteration of smell).” And in recognizing more recently identified symptoms, the guidance also newly mentions that additional emerging symptoms, such as cognitive dysfunction, can also be assessed by sponsors, if appropriate.
• For two common symptoms – vomiting and diarrhea – the FDA has revised its assessment recommendations. The agency no longer recommends that patients report these symptoms using a frequency scale within a 24-hour recall period. Instead, patients should be directed to document each of these events “promptly after” each episode occurs. To accommodate this change in recording frequency—and to document other frequent events or episodes—the guidance explains that sponsors may want to consider “an event-driven electronic diary rather than a diary completed once daily with a 24-hour recall.” Again, the guidance informs sponsors that alternative items and response options can be considered for these two symptoms. However, the suggested alternative approach – “a verbal rating frequency scale with a 24-hour recall period” – differs from that suggested in the prior version, which was to ask the subject to “rate the symptom severity at its worst.”
• The section on endpoint selection now mentions “COVID-19 rebound.” In the May 2022 CDC Health Advisory cited in the guidance, Covid-19 rebound is defined as the “recurrence of symptoms or a new positive viral test after having tested negative,” independent of treatment and regardless of vaccination status. Per the advisory (and loosely referenced in the guidance), the reported cases of recurrent illness have been mild, with symptoms improving or resolving without additional treatment in a median of three days. The guidance states that sponsors should select a time point(s) for the clinical endpoint that considers up-to-date knowledge of the time course of COVID-19-related symptom onset or resolution, including the potential for Covid-19 rebound.
• The FDA also tweaked the discussion on assessing clinical benefit to more accurately reflect the natural progression of Covid-19. The guidance now states that an appropriate endpoint for treatment trials could be the time to sustained “symptom alleviation or resolution” assessed over an appropriate duration. This replaces the previous statement, which referred instead to the time to sustained clinical recovery.
• In the final section of the guidance, “Additional COVID-19-Related Assessments,” the agency now addresses symptom clusters. Examples of this concept listed in the guidance include respiratory or digestive COVID-19-related symptom clusters. The document states that severity of these symptom clusters could be assessed using a patient-reported global impression item. Additionally, this section also contains a new note that, depending on the intent of the clinical trial assessment, sponsors can consider “frequency of patient-reported global impression items which may be less frequent (i.e., weekly) with differing recall periods including now, past 24 hours, or past week.”

Analysis

• Interestingly, not one organization or company submitted feedback to the docket when the previous version of the guidance was posted. One potential reason for this lack of input is that the FDA may have already been in close communication with sponsors who were working to develop products to prevent or treat COVID-19. As a result, it’s possible that sponsors with questions or concerns about symptom assessment obtained clarification through informal means of communication with FDA reviewers.
• This final guidance does not specify symptom assessment for vulnerable populations. While the FDA’s recently updated guidance on Covid-19 product development states that “Age is one of the strongest risk factors for severe COVID-19 outcomes,” and urges sponsors to enroll “older adults, including individuals 75 years of age and older” in clinical trials, this guidance on symptom assessment does not mention this group of adults, nor does it discuss specialized symptom assessment for other vulnerable populations, such as patients who are pregnant or lactating. The guidance also does not specify any differing expectations in symptom monitoring for patients at standard or high risk for serious disease.
• What’s next? This guidance is immediately in effect as of the date of publication. This leaves one remaining Covid-19-era guidance document for the FDA to update. That guidance — Container Closure System and Component Changes: Glass Vials and Stoppers — has been extended until August 7.

To contact the author of this analysis, please email Rachel Coe ( [email protected]).
To contact the editor of this analysis, please email Chelsey McIntyre ( [email protected]).

Key documents and dates

• 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