FDA updates guidance on developing drugs for Covid-19, replacing pandemic-era version

Last week, FDA published the third update to its guidance on the development of products to prevent or treat Covid-19. This update is the first to occur since the end of the public health emergency (PHE) and will now remain in effect indefinitely. Revisions to this guidance reflect both the growing body of knowledge related to Covid-19 and some subtle shifts in FDA policy over the past few years.

FDA’s transition away from public health emergency (PHE)-related guidance documents

• 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. [Read Agency IQ’s complete breakdown of the FDA’s PHE guidance documents here.]

FDA’s guidance on developing products to prevent or treat Covid-19

• Of the five guidance documents that received an extension, one addresses the development of drugs and biological products for Covid-19. That guidance, first issued in May 2020, was released at a time when there were no FDA-approved drugs to treat Covid-19, and the standard-of-care for treatment relied on clinical management of symptoms and supportive care (e.g., supplemental oxygen, mechanical ventilation). Likewise, while the FDA did offer initial recommendations on the selection of safety and efficacy endpoints in the guidance, the natural history of Covid-19 was not yet well understood, nor was there consensus on why symptoms manifested differently in different individuals or how long symptoms typically last.
• About one year after its initial publication, FDA updated the guidance in February 2021. Like the first version, the updated guidance was issued as direct-to-final. However, the revision provided much more detail given the amount of information on Covid-19 that was gained between May 2020 and February 2021. For example, reflecting the development of a new standard of care for Covid-19, the guidance stated that “in some situations, use of an active control with a superiority or non-inferiority design may be appropriate.” It also stated that companies should consider whether an investigational product might interact with an administered vaccine for Covid-19. Furthermore, the guidance offered a list of updated clinical outcome measures and offered insight on FDA’s evolving view of decentralized clinical trials and the use of real-world data to supplement trials.
• The guidance also provided insight on new issues that had arisen since the first version of the guidance was published; for example, the potential for drug resistance and the impact of virus shedding and immune response. These topics were covered in the body of the guidance and were addressed in two new appendices. “Using an antiviral drug to treat Covid-19 may contribute to the emergence of viruses with reduced susceptibility to the drug or to other approved or investigational drugs,” the FDA explained. As a result, the guidance advised sponsors to characterize potential drug resistance pathways and the potential for cross-resistance in nonclinical and clinical studies.
• FDA also offered its perspective on the release of interim study results—something that happened often (and sometimes without permission) during the pandemic as companies sought to provide public health officials with the best information available. “Releasing interim results could have ramifications on the integrity of the ongoing trial and the ability to collect reliable and interpretable data needed to support regulatory decision-making,” the FDA wrote. It advised sponsors to prospectively plan these analyses and use processes such as an independent Data Monitoring Committee (DMC) to ensure integrity. Further, a “trial should aim to minimize missing data” by distinguishing between discontinuation from the study drug and withdrawal from study assessments.
• Lastly, the revised guidance briefly discussed trials meant to assess drugs intended for prevention of Covid-19. For such studies, the FDA recommended a primary endpoint of laboratory-confirmed SARS-CoV-2 infection with or without symptoms. In addition, the guidance suggested that sponsors conduct antibody testing throughout the study to identify asymptomatic cases.

Now, the FDA has issued its first post-PHE version of this guidance

• Although the previous version of the guidance was revised to remain in effect until March 7, 2024, it has now been replaced. On November 23, the FDA published a new, direct-to-final post-PHE version of the document. Those familiar with previous versions of the guidance will find that much of the content has remained the same. As before, the guidance provides recommendations on drug development for COVID-19 across five domains: population, trial design, efficacy endpoints, safety considerations and statistical considerations.
• This latest final guidance is intended to remain in effect indefinitely, diverging from previous versions which were confined to the duration of the PHE. Also of note, the current guidance does not explicitly exclude master protocols from its scope, whereas the previous versions did.
• The FDA has streamlined its recommendations for sponsors enrolling patients in clinical trials. While the guidance aligns in principle with previous versions, it no longer provides a laundry list of conditions that could place a patient at high risk for complications from Covid-19. Instead it notes that, overall, clinical trials for products intended to treat Covid-19 should accurately reflect the product’s intended use. For instance, if the product is intended to prevent hospitalization, patients at a high risk of progression to severe disease should be enrolled in the trial. The guidance also newly defines four subgroups of patients that should be considered for inclusion in trials to evaluate products to treat Covid-19: 1) Non-hospitalized individuals at standard risk of progression to serious disease, 2) Non-hospitalized individuals at high risk of progression to serious disease, 3) Hospitalized individuals requiring supplemental oxygen, and 4) Hospitalized individuals with respiratory failure.
• The agency has also taken a stronger stance on enrolling patients with organ impairment. While the previous version stated that patients with kidney or liver dysfunction should be enrolled as long as the pharmacokinetics (PK) for the drug in such patients is “adequately understood,” the new guidance is phrased to indicate that, moving forward, the PK in these patients should be understood. The FDA now states that “Studies to characterize the effect of extrinsic factors (e.g., drug-drug interactions) and intrinsic factors (e.g., renal impairment or hepatic impairment) on the pharmacokinetics of a drug should be conducted early in development to inform the management of drug-drug interactions and inclusion of individuals with renal and/or hepatic impairment in clinical trials as appropriate.”
• The guidance carries a similar revision regarding the inclusion of pregnant individuals. In contrast to the previous version, which called for the inclusion of pregnant individuals in phase 3 trials “when appropriate,” this new version emphasizes that sufficient work should be conducted early on to facilitate the inclusion of pregnant individuals in later stage trials. Per the guidance, this includes the conduct of “adequate nonclinical studies,” though no further detail is offered.
• Regarding trial design: Most of the recommendations in the updated guidance are consistent with the February 2021 version. One noteworthy addition is the statement that “Sponsors are encouraged to use quantitative clinical pharmacology approaches that leverage all available information for selection of dosing regimen(s) to be evaluated in clinical trials.” While the concept of quantitative systems pharmacology (QSP) has been around for several decades, the prospect of actually using these models in regulatory applications is still quite new. QSP’s recent transformation from theory to reality is largely owed to recent advancements in real-world data utilization, increased adoption of decentralized approaches which allow for real-time monitoring of patients in clinical trials, and the rapid evolution of machine learning and generative artificial intelligence (AI) technologies.
• Regarding vaccination status: The new document expands upon a previously simple recommendation to determine vaccination status for patients enrolled in clinical trials. In addition to collecting information regarding vaccination status and timing of vaccine administration prior to trial enrollment, the revised guidance states that if a trial enrolls a mixture of subjects with “different baseline severity levels, baseline medication use, and/or vaccination statuses, sponsors should conduct subgroup or interaction analyses to assess for differential treatment effects.” It also recommends sponsors conduct and provide FDA with analyses “describing concomitant medication use and changes in vaccination status during the trial overall and by treatment arm.”
• Another small (but useful) change made to the new version of the guidance is that the FDA has newly defined what it means by “sustained clinical recovery.” In the previous version of the guidance, FDA included this term on its list of potential clinical outcome measures, but offered no further detail on how it defined this measure. In the latest version, FDA has replaced this term with “sustained symptom alleviation or resolution” which it defines as “no key COVID-19-related symptom scored higher than a prespecified threshold over a clinically meaningful time period (as documented using a patient-reported outcome instrument)” in the context of trials evaluating non-hospitalized patients. AgencyIQ notes that this clarification may stem from the growing number of reports suggesting that Paxlovid (Nirmatrelvir/ritonavir; Pfizer), an antiviral drug currently used for the outpatient treatment of Covid-19, may be associated with a “rebound” of symptoms or viral shedding in more patients than originally thought.

Analysis

• The update to this guidance document appropriately reflects our expanding understanding for Covid-19 and the drugs used to treat and prevent it. The agency has made small but important changes throughout the guidance, incorporating the growing understanding for the interplay of various factors, including vaccination status, baseline medication use, underlying conditions, and more, on the outcomes of patients with Covid-19. This builds upon the revisions that were made almost 18 months earlier, during which the FDA incorporated evolving information on the treatment of Covid-19 and the development of variants and resistance. It remains to be seen how often the FDA will continue to update this guidance as new information emerges on the treatment and prevention of Covid-19.
• One topic that is still not covered by this, or any, guidance – the treatment or prevention of Long Covid-19. At the beginning of all versions of the guidance, the FDA has consistently clarified that preventative vaccines and convalescent plasma are not within its scope. With this newest revision, the agency has added Long Covid-19 to the list of topics that are not within scope. Of note, the FDA does not currently have a guidance (draft or final) on developing drugs for this condition, and such a guidance is not currently listed on the CDER Guidance Agenda published in July 2023. The agency did hold a public meeting in April on “ Patient-Focused Drug Development for Long COVID” and has also provided grants related to the study of this condition. Separately, the NIH has a full research program, RECOVER, with the goal “to rapidly improve our understanding of and ability to predict, treat, and prevent PASC (post-acute sequelae of SARS-CoV-2), including Long COVID.” However, it is unclear whether the agency is planning to take any further actions in this area.
• There are several small changes to the language used over the three versions of the guidance which reflect overarching changes in FDA policy over that same time. For example, the way that diversity in clinical trials is discussed in the guidance has evolved. While previously the guidance stated that sponsors should select clinical trial sites that include “geographic locations with a higher concentration of racial and ethnic minorities to recruit a diverse study population,” the new guidance utilizes a broader definition of what “diversity” means (i.e., not just race or ethnicity) and instead notes that study site locations should be selected “to facilitate enrollment of a diverse study population.” Similarly, while the original version of this guidance noted that the agency would consider decentralized trials “under certain circumstances,” the subsequent revision acknowledged the importance of decentralized trials to Covid-19 drug development, and the newest revision continues to recognize that this type of trial will likely play a role in drug development.

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

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