New COVID-19 Guidances for Drugs and Biologics: FDA Provides Further Clarity on the Pre-IND Process and Clinical Trial Expectations

Two new guidances, both issued by FDA on May 11, 2020, focus on drugs and biological products proposed for use against COVID-19.  The first is entitled COVID-19 Public Health Emergency:  General Considerations for Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological Products (the “Pre-IND Guidance”) and the second is COVID-19:  Developing Drugs and Biological Products for Treatment or Prevention (the “Clinical Guidance”).  Both provide more insight into FDA’s expectations for drug development programs for new treatments for COVID-19.  FDA intends that these guidances will remain in effect only for the duration of the COVID-19 public health emergency, although FDA expects to revise and reissue the Clinical Guidance within 60 days of termination, taking into consideration lessons-learned from its experience and comments received to the extent appropriate.

In the Pre-IND Guidance, FDA cites the numerous inquiries and applications it has received from prospective sponsors and the Agency’s need to obtain key information in order to efficiently address proposals and ensure they are properly evaluated in a timely manner.  It may be that the Agency has been inundated with pre-IND meeting requests (as well as requests for an Emergency Use Authorization (“EUA”) under its Coronavirus Treatment Acceleration Program (“CTAP”) many of which do not include the type of information essential to evaluation.  FDA’s CTAP web page states that as of April 16, 2020, FDA had received 950 inquiries and proposals for COVID-19 related drug development.  These guidances appear to be an effort to improve the quality of those inquiries and proposals, and to highlight that the vast majority of proposed therapies are more appropriate for the investigational new drug (“IND”) route rather than the EUA route which requires more fully developed data to support.

The Pre-IND Guidance

For sponsors that already have an active IND for a drug in development, FDA recommends submitting a new pre-IND meeting request for a proposed COVID-19 indication, rather than amending their current submissions, in order to allow FDA to quickly identify, prioritize and assess the proposed study.  FDA also recommends that drug development discussions be initiated under the pre-IND program, rather than a pre-EUA request, noting that submitting a pre-IND request does not preclude submitting an EUA request if it becomes appropriate and that, in most cases, at the time a sponsor seeks to initiate discussion with FDA the available information is insufficient to determine effectiveness.  Until enough information is available for FDA to make a determination that the potential benefits outweigh the potential risks, an EUA is not the appropriate mechanism.

The Pre-IND Guidance lays out a list of general content recommendations most of which are comparable to what would be expected for any pre-IND meeting (e.g., drug name and description, brief description of manufacturing, proposed indication, existing pharmacokinetic, nonclinical and clinical data, suspected mechanism of action).  FDA cautions that while it may, in the case of a proposal for an unapproved use of an approved drug, exercise some flexibility in the type and amount of nonclinical data required to proceed, typically nonclinical in vivo data will be required.  The guidance also describes the types of nonclinical studies needed for small molecule drugs and biological products, and calls out inhalation drugs, in particular, as requiring toxicology studies to support the proposed dose and route of administration.   FDA also advises, however, that for cellular and gene therapies, blood products, vaccines and other complex biological products regulated by the Center for Biologics Evaluation and Research (“CBER”), there may be additional considerations. Inclusion of a draft protocol in the pre-IND meeting request is strongly encouraged.

Specific to COVID-19, FDA notes that some sponsors may seek development advice in the very early stages, and directs sponsors who do not yet have antiviral activity information, but have reason to believe the drug may have potential activity against the COVID-19 virus to the National Institutes of Health (NIH) Division of Microbiology and Infectious Diseases web page which contains information about preliminary screening activities that may be available.

Finally, the guidance provides the email addresses for questions about the process for CDER-regulated drugs and for CBER-regulated drugs (COVID19-productdevelopment@fda.hhs.gov and CBERProductJurisdiction@fda.hhs.gov, respectively), as well as one for sponsors unsure of how their drug would be regulated ( COVID19-productdevelopment@fda.hhs.gov ).

The Clinical Guidance

Vaccines and convalescent plasma are specifically excluded from the scope of the Clinical Guidance which focuses on Phase 2 and Phase 3 studies of drugs and other biologics (we refer to both as drugs unless a distinction is necessary), with recommendations specific to COVID-19 studies.  The key considerations covered include study population, trial design (including length of study, use of standard of care (“SOC”), early stopping criteria), efficacy endpoints, and safety and statistical considerations.  Many of the recommendations are not unique to studies involving COVID-19.

For treatment trials, FDA recommends that the baseline severity of the enrolled population be documented and provides criteria for defining categories of severity.  The population should include persons at high risk of complications such as the elderly, those with underlying cardiovascular or respiratory disease, diabetes, or chronic kidney disease, and the immunocompromised.  Due to the disproportionate effects seen on the elderly, sponsors are directed to consider conducting trials in nursing homes and other elder care facilities.  The need for racially and ethnically diverse populations is noted.  Specific to COVID-19, the possible need to close some sites and open new ones during the study due to the expected fluctuation of disease in regions should be anticipated and addressed in the study design.  FDA notes that children should not be categorically excluded, and encourages enrollment of pregnant and lactating individuals in Phase 3 studies.

It is no surprise that FDA strongly recommends that drugs for preventing or treating COVID-19 be evaluated in randomized, placebo-controlled, double-blind clinical trials using a superiority design, and that background SOC be maintained in all treatment arms.  The evolving nature of the SOC should be taken into consideration, as well as whether the SOC has the same mechanism of action as the investigational agent.  FDA advises limiting in-person data collection to the extent possible due to infection control concerns.  The appropriate length of the study will depend, in part, on the population being treated with shorter arms for trials involving mechanically ventilated patients (e.g., four weeks) and longer for studies of those who are less ill.  Whether it is appropriate to move directly to conducting a trial of sufficient size and design to provide substantial evidence of effectiveness and characterization of safety or a smaller pilot study is needed first will depend on how much preclinical and preliminary clinical evidence is available and how compelling it is.

FDA also encourages sponsors to use an independent data monitoring committee (“DMC”) and take into consideration the possibly rapid enrollment rate and incorporating a potential pause in enrollment to allow the DMC to assess data before dosing the entire study population.  Prospectively planned stopping criteria are also recommended.

In its recommendations on efficacy endpoints, FDA notably states that virologic measures may be appropriate for a Phase 2 trial, but will not be appropriate as a primary endpoint in a Phase 3 trial because of the lack of an established predictive relationship between viral reduction and the clinical benefit of how a patient feels, functions or survives.  FDA considers viral measurements as appropriate secondary endpoints in Phase 3 trials.

Examples of important clinical outcome measures in treatment trials are provided and include all-cause mortality, respiratory failure (e.g., need for mechanical ventilation), a move to ICU or hospitalization, objective measures of improvement (e.g., return to room air or other baseline oxygen requirement), and resolution of symptoms.  The choice of endpoint and the time of measurement should take into consideration the population being studied.  FDA advises that potential relapses should be addressed in the endpoint definition to ensure an adequate assessment of the durability of response.

For prevention trials, FDA states that the primary endpoint should be the occurrence of laboratory-confirmed infection with the virus (with or without symptoms) or infection with symptoms through a specified time point.  FDA also notes that ascertaining whether COVID-19 is milder in those receiving preventive treatment is of interest and recommends collecting clinical outcome data (e.g., hospitalization) and data on symptoms for this purpose.

Among the statistical considerations listed in the guidance are a few specific to COVID-19.  In particular, FDA recommends that if the study enrolls a mix of patients with varying baseline severity levels, a subgroup or interaction analysis by baseline severity should be conducted to assess for differences in treatment effect.