On May 11, 2020, the U.S. Food and Drug Administration (“FDA”) issued new guidance on the development of drugs and biologics to treat or prevent COVID-19: COVID-19 Public Health Emergency: General Considerations for Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological Products (“Pre-IND Guidance”) and COVID-19: Developing Drugs and Biological Products for Treatment or Prevention (“Clinical Development Guidance”) (collectively, “the Guidances”). These two Guidances follow other recent efforts by FDA, such as the launch of the Coronavirus Treatment Acceleration Program (“CTAP”), to support the development of potential COVID-19 therapies.
Taken together, the Guidances make clear that sponsors developing COVID-19 pharmaceutical products should develop plans to study the products in human clinical trials and to engage with FDA to obtain the Agency’s feedback on the development program, including trial design, study populations, efficacy endpoints, safety issues, and statistical considerations. These Guidances reflect FDA’s strong preference for randomized, double-blind, placebo-controlled trials, as opposed to the use of expanded access programs or premature requests for an emergency use authorization (“EUA”). Given the volume of COVID-19 submissions FDA has received, FDA strongly encourages sponsors to consider the Agency’s recommendations carefully as they build their drug development and regulatory strategies.
Pre-IND Guidance
In the Pre-IND Guidance, FDA provides recommendations on the content of submissions for potential COVID-19 drugs and biological products and the process that FDA intends to use to review those submission. Importantly, FDA recommends that all interactions with the Agency on COVID-19 drugs and biologics begin with a pre-IND meeting request, rather than a pre-EUA submission or an EUA request. FDA makes clear that EUAs for COVID-19 drugs and biologics will not be issued without clinical data supporting the safety and effectiveness of the product in COVID-19 patients. FDA notes that beginning with the pre-IND process does not preclude submission of an EUA in the future but notes that EUA submissions are appropriate only where the product is a “good candidate for an EUA.” Against the backdrop of the overwhelming number of EUA submissions that FDA has received to date, the Agency is sending a strong signal that requests for EUAs with insufficient human clinical data should not be submitted.
With respect to the content of pre-IND submissions for potential COVID-19 products, FDA provides recommendations for clinical, non-clinical, and quality considerations. FDA strongly emphasizes safety information, particularly for first-in-human drugs and biologics, and provides additional recommendations specific to antiviral and inhalational drugs.
From a process perspective, FDA makes clear that sponsors should submit COVID-19 proposals only through a dedicated COVID-19 pre-IND request, not through active applications for other conditions. Sponsors should cross-reference any existing INDs, new drug applications (“NDAs”), or biologics license applications (“BLAs”) for the drug product, but should not submit COVID-19-related information to existing INDs, NDAs, or BLAs. This approach is designed to help FDA quickly prioritize and assess proposed COVID-19 trials and to provide timely feedback. FDA also has streamlined the pre-IND meeting procedures for COVID-19 drugs and biologics. Rather than the usual 2-step process for submitting a meeting request followed by a briefing package, FDA has requested submission of the full briefing package, including specific questions for the reviewers, with the original meeting request. The Agency also explained that the review teams generally will be providing written responses only (“WROs”), rather than regularly granting meetings. Although FDA indicates the importance of “early and thorough review,” FDA signals that sponsors should not file prematurely, suggesting that timing of submissions should be optimized to ensure the most effective use of sponsor and FDA resources. FDA plans to expedite and prioritize requests based on scientific merit and completeness of the submission.
Clinical Development Guidance
The Clinical Development Guidance provides recommendations regarding the design of phase 2 or 3 trials of drugs for the treatment or prevention of COVID-19. Consistent with the theme of the Pre-IND Guidance, FDA “strongly recommends” randomized, placebo-controlled, double-blind clinical trials, with background standard of care maintained in all treatment arms. FDA acknowledges that the standard of care for COVID-19 is likely to change as new data regarding potential treatments emerges and that sponsors may need to incorporate add-on designs, active comparators, or other revisions where appropriate.
FDA recommends study populations that include a range of patients (e.g., persons at high risk of complications) and reflect the general population (e.g., weighted for disproportionate effect in older adults). For prevention trials, FDA recommends pre-exposure studies in high-risk populations (e.g., health care workers, first responders) or post-exposure studies in individuals with documented exposure to COVID-19 cases. For treatment trials, FDA provides population recommendations and further encourages evaluating COVID-19 severity based on proposed severity criteria, which mirror the National Institute of Health’s (“NIH’s”) criteria in its COVID-19 Treatment Guidelines. The Clinical Development Guidance provides additional recommendations for potential clinical outcome measures, which may vary depending on baseline disease severity or other factors, as well as developing an appropriate safety database and addressing potential statistical considerations.
Sponsors of potential COVID-19 pharmaceutical products should review FDA’s recommendations and plan early discussions with the relevant review division to address any concerns or potential changes to development plans.
For concerns regarding how the public health emergency might impact the conduct of non-COVID-19 clinical trials, sponsors should consult FDA’s separate guidance on the Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency (see our client alert on earlier versions of this guidance).
Scope and Duration of the Guidance Documents
The Guidances provide insights for many drugs and biological products that are being developed for COVID-19. FDA notes, however, that the Clinical Development Guidance is focused on drugs with direct antiviral activity or immunomodulatory activity and does not apply to preventative vaccines (which raise additional considerations around subject selection, safety monitoring, and effectiveness evaluation) or convalescent plasma (which is covered by separate guidance). In both Guidances, FDA also notes that development of certain types of biological products, such as cellular and gene therapies and blood products, raise additional considerations and should be discussed with the Center for Biologics Evaluation and Research (“CBER”).
Consistent with its policy for all COVID-19 guidance, FDA is implementing these Guidances immediately and without prior public comment, although interested parties still may submit comments for consideration by the Agency. FDA intends the Pre-IND Guidance to remain in effect only during the COVID-19 public health emergency, but the Clinical Development Guidance may be revised and extended beyond the public health emergency to continue assisting COVID-19 clinical development efforts.
If you have any questions concerning the material discussed in this client alert, please contact the following members of our Food, Drug, and Device Practice Group.
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