Following a series of updated and new guidance documents to address COVID-19, the FDA has released new recommendations on how sponsors can request early-stage meetings with the FDA and the data they’ll need to provide.
By Kedest Tadesse, MS, RAC
How things work now
Under the Prescription Drug User Fee Act (PDUFA), there are four types of meetings a sponsor can request to interact with the FDA. A pre-IND meeting is one form of a Type B meeting that allows for an early interaction with the FDA to discuss the company’s proposed drug development program. These meetings can take place face-to-face at the FDA, through teleconference or as a written response only (WRO).
Generally, a sponsor will submit a meeting request letter (MRL) that includes information about the product, specific objectives for the meeting and a list of questions the sponsor would like to discuss with the FDA. The agency will then consider and respond to the MRL within 21 days to deny, grant or provide a written response to the request. If a meeting is granted face-to-face or as a WRO, it will be scheduled 60 days from the receipt of the MRL.
The sponsor is then required to submit a meeting briefing package no later than 30 days before the scheduled meeting or WRO. The package should provide summary information of the product and all the necessary and supplementary information needed for the FDA to answer the sponsor’s questions.
Pre-IND meetings allow for the sponsor to confirm the drug development plan laid out is acceptable to the agency and would support an eventual approval decision. This allows for any modifications to the drug development program and more specifically to the first study protocol prior to the submission of an Investigational New Drug Application (IND).
As the FDA works to confront COVID-19, new guidance issued by the agency aims to provide recommendations to companies seeking feedback on their proposed clinical development programs. There has been substantial interest in clinical development to date. The FDA announced on May 12th that it is overseeing more than 130 clinical trials for COVID-19-related drugs and biological products.
The guidance document details the FDA’s recommended process for requesting and making use of pre-IND meetings.
The meeting request letter (MRL) and briefing package should be submitted as one package. Requests will be expedited and prioritized based on upon the completeness of the submission and scientific merit.
Sponsors that are expanding the indication of their drug to include COVID-19, but that already have an open IND, pending pre-IND request or IND under review are advised by the FDA to submit a new request instead of an amendment. Sponsors are allowed to refer to already submitted applications. A new request allows for the FDA to quickly prioritize and review requests related to COVID-19. Additionally, there might be cases where the new request is assigned to a new review division, and a new request allows for a quick assignment of the review.
The FDA said it recommended the use of pre-IND requests instead of pre-emergency use authorizations (pre-EUA). The EUA process requires an established benefit risk profile which generally is generally determined later on in the drug development process. Thus, pre-IND meetings allow for a more efficient development process. Initiating discussion as a pre-IND doesn’t preclude from future EUA requests. EUAs will be considered when information to evaluate risk and benefit is available under an IND.
The content of a pre-IND meeting request and briefing package in the context of COVID-19 is the same as an ordinary application. Details about the drug including API, characteristics, mechanism of action (MOA), manufacturing, dosage, pharmacokinetic information, nonclinical and clinical is required.
Pre-IND meeting request submissions can be made through the electronic submission gateway, CDER’s NextGen portal or via email to CBER.
While the guidance notes the FDA is flexible in the type and amount of data required, there are non-negotiable requirements for an unapproved drugs and approved drugs with new routes of administration. In such cases, in vivo data are required. Formulation and nonclinical pharmacology and toxicology data should also be included in the package. For products that are already approved, labeling of the approved product or cross-referencing is sufficient for submission.
A summary of results of in vitro and in vivo studies including a brief methodology should be submitted. Additionally, a substantiation is required for novel drug excipients.
Generally, the FDA requires for animal studies to have equivalent duration to the proposed clinical trial. For example, if the clinical trial has a planned duration of 6-months, the animal studies should also have the same duration. In this case, the FDA also provides an alternative method: Reduce, refine, replace (3Rs) where feasible. This is acceptable if the FDA considers the alternative method to be equivalent to the animal test method. Sponsors should discuss such methods with the FDA prior to initiating studies.
Standard safety pharmacology studies (i.e., cardiovascular, respiratory and central nervous system (CNS) assessments) should also be included. For small molecules, toxicology studies should be conducted in two species, rodent and non-rodent. Furthermore, genetic toxicology including an AMES reverse mutation assay and a second in vitro assessment is required. For biological products, toxicology studies should include a species and a tissue cross reactivity assay in human tissues where feasible.
Pivotal nonclinical studies should be conducted according to good laboratory practices (GLP) with the standard toxicology and toxicokinetic endpoints. Route of administration, drug substance and formulation in nonclinical studies should be the same to the planned clinical trial.
The clinical section of the request and package should include a justification for the proposed dose and route of administration based on the nonclinical data obtained. If the product has been used in humans, a summary of safety data should be included.
The clinical study protocol for Phase 2 and 3 trials should be randomized, placebo-controlled and double-blind using a superiority design. A draft protocol should be submitted for review. This includes overall design, inclusion/exclusion criteria, endpoints, safety assessments and statistical consideration plans.
Due to safety concerns in COVID-19 patients, the FDA recommends the use of an independent data monitoring committee (DMC). Sponsors should submit a detailed safety monitoring plan in the pre-IND package.
Antiviral drug products identified based on cell culture antiviral activity data and animal models do not reliably predict benefit in humans. Sponsors should establish effectiveness based on the previously published guidance on demonstrating substantial evidence of effectiveness. Furthermore, if the antiviral is in early stages but has potential activity against SARS-COV-2, sponsors should consult the National Institutes of Health (NIH).
One facet the guidance does not address is timing. There is no clear timeline established for granting a request or providing a WRO. It is yet unclear if the FDA will follow its previously established timeline for response or if it will expedite pre-IND meeting related to COVID-19.
However, based on prior FDA statements and the agency’s Coronavirus Treatment Acceleration Program (CTAP), sponsors should be ready to respond to any additional information requests from the FDA and prepare for any immediate teleconference meetings almost immediately after submission.
The guidance is also notable for its efforts to accelerate pre-clinical testing. Sponsors should consider alternative methods that are acceptable discuss them with the agency as early as possible. Also notable is the guidance document’s stance on EUAs. The FDA encourages sponsors to seek pre-IND meetings instead of pre-EUAs to discuss the drug development and discuss the path forward that will lead to EUA.
For approved products intended to be repurposes for treating COVID-19, it is critical to cross-reference to previous applications appropriately. First, making sure there is proper authorization to cross-reference if the application is no longer held by the same sponsor. Second, sponsors should make sure the cross-referenced applications is up-to date and provides all the information the agency needs to provide clear answers in the WRO. An application submitted using the Electronic Submission Gateway will allow for an easy cross-referencing and adds ease to the reviewer.
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