The Food and Drug Administration has the difficult task of trying to balance the urgent need for therapeutics for the treatment of the Coronavirus Disease 2019 (COVID-19) with protecting the public health.  While the agency has moved fairly quickly, with various degrees of success when it comes to diagnostics, personal protective equipment and ventilators, FDA has taken a more measured approach with drugs and biological products.  This is evidenced by the fact that the agency has only issued five Emergency Use Authorizations (EUAs) for therapeutics as of May 22, 2020.¹  On the other hand, as of the writing of this Bulletin, FDA has authorized 105 tests under EUAs (92 molecular, 12 antibody and 1 antigen test).²   There are no FDA-approved drug products to treat COVID-19.

At the end of March 2020, FDA established the Coronavirus Treatment Acceleration Program (CTAP) to provide regulatory advice, guidance and technical assistance to potential sponsors seeking to develop drugs and biologic therapies for COVID-19.³   However, the agency did not provide any written guidance concerning the type of information that sponsors must submit for the agency to be able to evaluate their products.⁴

After approving 144 clinical trials and reviewing another 457 development programs for therapeutic agents in planning stages, on May 11, 2020, FDA issued a guidance document on the development of drugs and biologics to treat or prevent COVID-19.⁵

The guidance document, titled, “COVID-19, Public Health Emergency:  General Considerations for Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological Products” (Pre-IND Guidance), provides “general considerations to assist sponsors in preparing pre-investigational new drug application (pre-IND) meeting requests for COVID-19 related drugs for the duration of the public health emergency.”  In the guidance, FDA also directs sponsors to “initiate all drug development interactions for COVID-19 related drugs through Investigational New Drug (IND) meeting requests,” instead of submitting a pre-emergency use authorization (pre-EUA) requests.⁶

According to FDA, most drugs being studied for the treatment or prevention of COVID-19 have insufficient data to receive authorization through the EUA mechanism, because there is not enough information to determine whether the “known and potential benefits outweigh the known and potential risks of the drug.”  Therefore, “many drugs proposed to be used under EUAs will more appropriately be the subject of INDs, with consideration regarding potential authorization under the EUA mechanism to follow as appropriate and warranted as more information is available.”

Summary of Key Recommendations

The Pre-IND Guidance provides sponsors with specific recommendations for the content of the pre-IND meeting request, including, nonclinical, clinical and quality recommendations.  FDA also provides specific recommendations for antiviral and inhalation drugs.

FDA will review and address any pre-IND meeting request “as a written response only meeting.”  According to the guidance, written response only communications are commonly used by the agency to respond to sponsor concerns instead of a face-to-face or teleconference meeting.

We highlight some of the key recommendations for each of these categories below.

General Nonclinical Considerations

FDA recommends that sponsors include certain data and information to allow the agency to evaluate the risks of the investigational drug, including information about the formulation and appropriate nonclinical studies.  While FDA notes that the agency may exercise some flexibility when it comes to the types and amount of data, “for proposals to proceed – when involving unapproved drugs, new doses, or formulations of an approved drug, or new routes of administration (e.g., inhalation) that have never been administered to humans –  typically nonclinical in vivo data will be needed to determine the risks of the drugs and to support safe starting doses in humans.”

For small molecule drugs, FDA notes that it expects a pre-IND meeting request to include data from “general toxicology studies in two species (at least one nonrodent) and genetic toxicology.”  The drug substance used in the toxicology studies should be identical to that proposed for clinical investigation.

General Clinical Considerations

FDA provides a list of several clinical considerations for sponsors developing drugs for the treatment or prevention of COVID-19.⁷   For phase 2 or 3 clinical trials, FDA “strongly recommends” that sponsors propose a “randomized, placebo-controlled, double-blind clinical trial using a superiority design.”  The agency believes that the variability of a clinical course of COVID-19 following treatment or prophylaxis and the lack of understanding of the disease can seriously affect the reliability of any conclusions based on uncontrolled data.  FDA notes that a sponsor should submit with the pre-IND meeting request a draft protocol that includes “phases of development, mechanism of action, overall design, and subject population with inclusion and exclusion criteria, endpoint, safety assessments, and brief statistical considerations.”

General Product Quality Considerations

FDA recommends that sponsors submit sufficient information to ensure acceptable quality (e.g., identity, purity, and strength/potency) of the investigational drug for the intended phase of development, as well as summary data and information supporting that the drug is stable for the duration of the clinical trial.  FDA also recommends that sponsors take into account specific product quality considerations given the limitations that may occur with severe COVID-19 patients (e.g., administration of oral dosage forms to intubated patients).

For sponsors of investigational antiviral drugs with limited antiviral activity information, FDA recommends consulting the National Institutes of Health Division of Microbiology and Infectious Diseases web page, which contains information about preliminary screening activities that may be available to potential sponsors of antiviral drugs in very early stages of development.

A pre-IND meeting request for a drug for inhalation (e.g., metered dose inhaler, nebulization) should include data to support the use of the proposed drug for this route of administration in humans.  This information should include “details of the proposed formulation (including drug product excipients), device for administration, and . . . . [Good Laboratory Practice (GLP)] toxicology studies with the intended route of administration (inhalation).  The GLP toxicology studies should support the proposed dose and duration.”

AGG Observations

• While there is an urgent need for treatments for COVID-19, FDA makes clear that it does not believe that an EUA is an appropriate mechanism for an investigational drug or biological product without some data to support the safety and effectiveness of the product.
• FDA expects that sponsors will conduct randomized, double-blind, placebo-controlled trials to determine the safety and efficacy of the drug for the treatment or prevention of COVID-19.
• The Pre-IND Guidance emphasizes the importance of putting together a quality submission when engaging with FDA. The agency will prioritize submissions based on “completeness and scientific merit.”  Moreover, given that FDA will respond to a pre-IND meeting request as “written response only meeting,” sponsors must try to anticipate and address any potential issues at the time of the initial submission, because there may not be an opportunity to provide additional information.
• As with the numerous guidance documents issued by FDA during the pandemic, the Pre-IND Guidance was implemented without prior public comment and will only remain in place for the duration of the public health emergency.

[1] See “FDA Combating COVID-19 with Therapeutics,” available at https://www.fda.gov/media/136832/download

[2] See FDA’s News Release “Coronavirus (COVID-19) Update: Daily Roundup May 21, 2020, available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-may-21-2020

[3] See Coronavirus Treatment Acceleration Program (CTAP), available at https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap.  As of April 16, 2020, FDA had received 950 inquiries and proposals concerning COVID-19 related drug development.

[4] See “Coronavirus (COVID-19) Update:  FDA Continues to Accelerate Development of Novel Therapies for COVID-19,” available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues-accelerate-development-novel-therapies-covid-19 . 

[5] Id.

[6] The guidance is available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/covid-19-public-health-emergency-general-considerations-pre-ind-meeting-requests-covid-19-related

[7] FDA also points to a separate guidance document, titled “COVID-19:  Developing Drugs and Biological Products for Treatment or Prevention” (May 2020), which provides additional recommendations on clinical endpoints in COVID-19 development programs.  Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/covid-19-developing-drugs-and-biological-products-treatment-or-prevention