These two guidances are intended to remain in effect for the duration of the COVID-19 public health emergency.

On May 11, 2020, the FDA issued two new guidances for industry and investigators of drugs and biological products proposed for use against COVID-19. These two guidances, “COVID-19 Public Health Emergency: General Considerations for Pre-IND[1] Meetings Requests for COVID-19 Related Drugs and Biological Products” and “COVID-19: Developing Drugs and Biological Products for Treatment of Prevention,” provide insight into the expectations of the FDA regarding new treatment drug development programs in the fight against COVID-19.

Through these two guidances, the FDA seeks to provide sponsors with an initial framework to help organize their Pre-IND meeting requests during the COVID-19 public health emergency as well as assist in the clinical development of the drugs for the treatment or prevention of COVID-19. FDA shares a joint objective with drug development sponsors—expediting development and approval of safe and effective therapeutic treatments for COVID-19.

COVID-19 Public Health Emergency: General Considerations for Pre-IND Meetings Requests for COVID-19 Related Drugs and Biological Products

This Pre-IND Guidance, issued to provide general considerations to assist sponsors in preparing Pre-IND meeting requests for COVID-19 related drugs, recommends that sponsors initiate all COVID-19 drug development interactions through IND meeting requests. The general principles set forth in the Guidance apply to drugs. The same general framework applies for cellular and gene therapies, blood products, vaccines and other complex biological products regulated by the Center for Biologics Evaluation and Research, with additional potential considerations.

In an effort to improve the quality and content of IND submissions and streamline prospective sponsor proposals, FDA recommends that drug development applications be submitted through the Pre-IND program rather than a pre-Emergency Use Authorization (EUA) request. Proposed sponsors are asked to use the Pre-IND program because, in general, drugs being studied for treatment or prevention of COVID-19 have insufficient data for the FDA to determine that the potential benefits outweigh the known and potential risks of the proposed drugs. The EUA process is designed for medical products that already have sufficient safety and efficacy data for FDA to approve use on an emergency basis to address the COVID-19 pandemic.

Per the Pre-IND Guidance, sponsors should include the following content and address the following issues when developing their meeting requests that will support clinical development programs:

• drug name,
• descriptions of active ingredients,
• description of the manufacturing scheme,
• proposed indication,
• dosage form and schedule,
• known or suspected mechanisms of action of the drug,
• pharmacokinetic information,
• summary of data and literature supporting the proposed use for treatment and prevention of COVID-19, and
• summary of pharmacology data and clinical information to support the proposed trial.

While FDA may exercise some flexibility in the types and amounts of data necessary to support drug development, for a proposal for an unapproved drug or new formulation of an approved drug to proceed, the sponsor will also have to submit nonclinical in vivo data to determine the risks of the drugs and support safe starting doses in humans. Moreover, any Pre-IND meeting requests for small molecule drugs, biological products and inhalation drugs should include toxicology reports supporting the proposed route of administration and dose. Additionally, sponsors seeking development advice for potential antiviral drugs in very early stages that do not yet have antiviral activity information (but believe the drug may have potential activity against COVID-19) should consult the National Institute of Health Division of Microbiology and Infectious Diseases website, which contains information about preliminary screening activities that may be available to potential sponsors.

Due to the numerous inquiries and applications for prospective sponsors for clinical trials for COVID-19, a well-prepared Pre-IND meeting request will enable more timely initiation of clinical trials under an IND. According to the FDA “it is essential that the Agency receive key information that will help enable us to efficiently address proposals and ensure they are properly evaluated and managed in a timely manner.”

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

This Clinical Guidance, issued to assist sponsors in the clinical development of drugs for the treatment or prevention of COVID-19, describes the FDA’s current recommendations regarding Phase 2 or Phase 3 trials for drugs under development to treat or prevent COVID-19. This Guidance focuses on the population, trial design, efficacy endpoints, safety considerations and statistical considerations for such clinical trials. The Guidance focuses on the development of drugs with direct antiviral activity or immunomodulatory activity. Preventative vaccines and convalescent plasma are not within the scope of the Guidance, nor does it provide general recommendations on early drug development in COVID-19, such as use of animal models.

Population

The sponsor of drugs to treat or prevent COVID-19 should consider a range of populations from outpatients to inpatients on ventilators. For treatment trials, the sponsor should document the diagnosis of COVID-19, such as laboratory confirmed documentation, and categorize the baseline severity of the enrolled population incorporating objective measures. FDA provided examples of severity criteria in the Appendix of the Guidance. For prevention trials, the sponsor should conduct trials in communities with documentation of circulating COVID-19 infections. Additionally, clinical trials should include a variety of persons at high risk of complications, such as pregnant and lactating individuals, the geriatric population, and racial and ethnic minority persons.

Trial Design

The FDA recommends that drugs for preventing or treating COVID-19 should be evaluated in randomized, placebo-controlled, double-blind clinical trials using a superiority design. Under certain circumstances, it may be appropriate to conduct decentralized and/or platform clinical trials. The sponsor should discuss this type of plan with the FDA. Further, in-person data collection should be limited. Trials should be long enough to evaluate safety and effectiveness reliably. According to the FDA, a four-week duration would likely be sufficient, although depending on the population, a longer duration may be appropriate. Additionally, a sponsor should use an independent data monitoring committee to ensure safety and trial integrity.

Efficacy Endpoints

The drug development program should evaluate the effect of the investigational drug relative to placebo on clinically meaningful aspects of the disease. The relevance and appropriateness of measures may depend on the population studied, the clinical setting and/or baseline severity. Additionally, the choice, time frame and interpretation of endpoints may differ depending on the population evaluated in the trial. Sponsors should address potential relapses in their endpoint definitions to ensure adequate assessment of the durability of response. The FDA also states that a virologic measure may be an acceptable endpoint for a Phase 2 trial, but will not be appropriate for a primary endpoint for a Phase 3 trial because there is no established predictive relationship between magnitude and timing of viral reductions and the clinical benefit of how a patient feels, functions or survives. Virologic endpoints may be assessed as secondary endpoints in Phase 3 trials.

Safety Considerations and Statistical Considerations

Per the Guidance, it is important for sponsors to include a broad population of subjects in adequate and well-controlled clinical trials to generate a safety database that will best inform the safe use of the drug. Sponsors should still conduct safety reporting outlined in FDA regulations and relevant guidance. Regarding statistical considerations, FDA recommends that if the treatment trial enrolls a mixture of patients with different baseline severity levels, sponsors should conduct subgroup or interaction analyses by baseline severity to assess for differential treatment effects. This approach should allow FDA to approve therapeutics specifically for population subgroups most likely to benefit from a particular therapeutic product.

Scope of Guidances

These two guidances are intended to remain in effect for the duration of the COVID-19 public health emergency, although within 60 days of the termination of the public health emergency the FDA intends to revise and replace these guidances with any appropriate changes based on comments received and the experience with implementation.

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Duane Morris has created a COVID-19 Strategy Team to help organizations plan, respond to and address this fast-moving situation. Contact your Duane Morris attorney for more information. Prior Alerts on the topic are available on the team’s webpage.

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If you have any questions about this Alert, please contact Frederick R. Ball, Patrick C. Gallagher, Ph.D., Brittany C. Wakim, any of the attorneys in our Life Sciences and Medical Technologies Industry Group, any member of the COVID-19 Strategy Team or the attorney in the firm with whom you are regularly in contact. 

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