Safety of trial participants is FDA’s top priority in ongoing clinical trials during the COVID-19 outbreak

On April 30^th, the U.S. Food and Drug Administration (FDA) hosted a webinar about conducting clinical trials during the COVID-19 outbreak. Jacqueline Corrigan-Curay and John Concato, both from the Office of Medical Policy, reviewed the crucial parts from the recently updated FDA guidance on conduct of clinical trials of medical products during COVID-19 public health emergency for sponsors, investigators and institutional review boards (IRBs). This article summarizes the key messages.

This guidance is built around three priorities:

1. 1. Ensure the safety of trial participants
   2. Preserve the integrity of the data of the trial
   3. Comply with good clinical practice (GCP)

It is important to note that this is general guidance. Particular situations with regard to the study population, investigational product, and trial phase or endpoint may require consultation with the appropriate FDA review division.

The first question that needs to be addressed is: should sponsors stop their trial?

• • Sponsors should consult with clinical investigators, IRBs or institutional ethics committees (IECs), and if applicable, data monitoring committees (DMCs)
  • Measures to protect the participant’s safety should be studied in each possible scenario: risk-benefit balance of continuing vs discontinuing the administration or use of the investigational product
  • Critical questions to be asked:
    • What can be done in terms of a protocol amendment?
    • Is there clinical trial staff available?
    • Are all supplies and technological tools for the trial still available?
    • Are the clinical operations staff available?
    • Can the investigational product be handled/stored/delivered/administered safely?

The responsible party for the trial will also need to evaluate alternative procedures to ensure effective data collection and monitoring (e.g., videoconferencing, sending samples to local laboratories, remote access to the patient's file).

Other important recommendations from the FDA are:

• Implementation of protocol modifications to eliminate immediate hazards as soon as possible, even before IRB/FDA approval (reporting required afterward)
• Exclusion of COVID-19 screening and results in the protocol unless one of the outcomes needs to be reported
• Any medical occurrence associated with the investigational product in humans, whether or not it is considered to be related to the drug, should be reported as an adverse event (AE), and that includes episodes of COVID-19 illness. All AEs will be incorporated in the FDA annual report, and the FDA recommends to collect as many details as possible so that the appropriate COVID-19 MedDRA code can be provided in the study report. As COVID-illness will generally be considered as not related to the study drug, it will not be necessary to report it as a suspected unexpected serious adverse reaction (SUSAR)
• Document, document, document!
  • Document all contingency measures and how they may impact the trial
  • In case of failing to collect the primary endpoint, priority should always be the safety of trial participants. Then, evaluate a possible update of the protocol and statistical analysis plan (SAP). It is important to remember that all modifications should be done before locking the database
  • Remote outcome assessments can be done, but consider training for all investigators, technical support for patients, and if this will be comparable to previous results already assessed
  • Consider centralized risk-based monitoring (remote access)
• An informed consent (IC) signature can be challenging to obtain according to GCPs when patients are in isolation (at the hospital or home), consider whether it is possible to electronically sign the document? If not, consider an alternative such as:
  • Consent collected by another healthcare worker in the room
  • Three-way phone or video call with an impartial witness (step-by-step guide for remote IC in the Q&A annex of the guidance)
  • Attestation by witness or photo of the signed IC

As a final note, the agency is expecting many protocol deviations due to this international public health emergency, but it will be flexible where appropriate.