By Matthew Pillar, Editor, Bioprocess Online
You’ve invested years, millions of dollars of other people's money, and an invaluable amount of your intellect to get your candidate trial-ready. You’re celebrating an FDA approval, or the success of early study results. Then along comes a pandemic, with a wrench in hand and ready to toss into your hard-earned clinical trial machine. Suddenly, your trial faces a new and unanticipated risk at every turn. How will the virus impact trial participation, and more importantly, the well-being of participants? Will it disrupt your investigational drug product supply? How might it alter your study design, data collection, and reporting protocols?
The FDA is aware of the unprecedented and unanticipated challenge you face, and as such, it issued guidance this week that offers sponsors advice on adjusting clinical trial protocols in the midst of the fast-spreading and ill-understood virus SARSCoV-2 and its resulting COVID-19.
The guidance addresses three core areas likely to be impacted by the pandemic; assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity.
Risks in all three of those areas can compound quickly.
Where confidence may exist in knowing how to treat a clinical trial patient stricken by the common cold, a flu virus, or any other known ailment (i.e., whether to maintain their participation or dismiss them from the trial, the impact of treatments administer outside the auspices of the trial, etc.), the same confidence can’t possibly be claimed of a COVID-19 positive trial participant. As New York City Mayor Bill DeBlasio mulls a city-wide shelter-in-place order, and with other cities—each with its own medical research hub—to surely follow, the impact of such orders, quarantines, site closures, and travel limitations can’t be discounted.
While patient safety and data integrity are paramount, the risks of disruption reaches beyond the potential impact on the study and its participants. Outsourced Pharma and BioProcess Online have extensively covered the implications of this pandemic on the biotherapeutics and API supply chains in general. Those supply chain interruptions can also shut down access to investigational product critical to the execution of your clinical trial, or make acquiring that produce a logistical challenge at best.
Regarding the potential impact of the pandemic and its effects on trial participants and, subsequently, trial data and feasibility, the FDA’s new guidance outlines a number of general considerations to help sponsors assure the safety of trial participants, maintain compliance with good clinical practice, and minimize risks to trial integrity. The considerations detailed in the 9-page guidance, which we encourage you to download and read in its entirety, are summarized here:
• Decisions on whether or not to continue trial recruitment, continue use of the investigational product for patients already participating in the trial, and change patient monitoring during the trial. FDA deems it critical that trial participants are informed of changes to the study and monitoring plans that could impact them.
• Determining whether the protection of a participant’s safety, welfare, and rights is best served by continuing a study participant in the trial as per the protocol or by discontinuing the administration or use of the investigational product or even participation in the trial.
• Evaluation of whether alternative methods for safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) could be implemented when necessary and feasible, and would be sufficient to assure the safety of trial participants.
• The potential need for additional safety monitoring of trial participants who no longer have access to investigational product or the investigational site (e.g. withdrawal of an active investigational treatment).
• Whether it is appropriate to delay some assessments for ongoing trials, or, if the study cannot be properly conducted under the existing protocol, whether to stop ongoing recruitment, or even withdraw trial participants.
• Whether or not to report COVID-19 screening procedures that may be mandated by the health care system in which a clinical trial is being conducted, and if that data should/could be collected as part of a new research objective.
• Engagement with IRBs/IEC (investigational review board/independent ethics committee) as early as possible when urgent or emergent changes to the protocol or informed consent are anticipated as a result of COVID-19. FDA encourages sponsors and investigators to work with their IRBs to prospectively define procedures to prioritize reporting of deviations that may impact the safety of trial participants.
• Whether implementation of alternative processes is consistent with your study protocol. FDA encourages documentation of the reason for any contingency measures implemented, changes in study conduct and duration of those changes, and indication of which trial participants were impacted and how those trial participants were impacted.
• How changes in study visit schedules, missed visits, or patient discontinuations might cause data disruption. FDA stresses the importance of capturing specific information in the case report form that explains the basis of the missing data, including the relationship to COVID-19 for missing protocol-specified information.
• Whether certain investigational products, such as those typically distributed for self-administration, may be amenable to alternative secure delivery methods when and if scheduled visits at clinical sites will be impacted. Plans for alternative administration of investigational products that are normally administered in a health care setting be reviewed by the FDA. In any case, existing regulatory requirements for maintaining investigational product accountability remain and should be addressed and documented.
• How consultation with the appropriate review division regarding protocol modifications for the collection of efficacy endpoints, such as use of virtual assessments, delays in assessments, and alternative collection of research-specific specimens, will be accommodated and documented.
• The review of management and/or statistical analysis plan amendments with the applicable FDA review division.
• The potential use of central and remote monitoring programs to maintain oversight of clinical sites, if planned on-site monitoring visits are no longer possible.
The guidance goes on to offer insight into trial policy and procedure revision and documentation, including the informed consent process, study visits and procedures, data collection, study monitoring, adverse event reporting, and changes in investigator(s), site staff, and/or monitor(s) secondary to travel restrictions, quarantine measures, or COVID-19 illness itself. Also covered are considerations for participant-specific documentation of study disruptions that occur due to COVID-19 control measures.
The FDA’s guidance indicates the agency is eager to facilitate the flexibility necessary in these extenuating circumstances. It also clarifies that its guidance is not legally-binding; should means should, however, it also advises firms wishing to take an alternative approach than that suggested in its guidance to contact the FDA and communicate their chosen approach. The full guidance is available here.