Protocol changes and deviations may be unavoidable to ensure the safety of trial participants during the COVID-19 crisis, the FDA says in a rare direct-to-final guidance released this week, and sponsors and investigators should examine alternatives to face-to-face trial procedures. 

The guidance, which takes effect immediately without prior public comment, makes several suggestions for trial modifications, including: 

• alternatives to in-person safety assessment (e.g., phone contact, virtual visits, alternative locations for assessment, including local labs or imaging centers), 
• direct-to-patient investigational product delivery,
• the collection of efficacy endpoint data, 
• replacing on-site monitoring with centralized or remote monitoring, and
• additional safety monitoring of trial participants if the trial is halted or treatment is discontinued. 

Many parts of trials, including assessments of clinical endpoints, are moving toward a remote design to reduce virus exposure and transmission, experts said last month at a WCG Clinical webinar on the impact of COVID-19 on trials. Michael Cioffi, senior vice president of clinical solutions and strategic partnerships at WCG, said there are things sponsors should take into consideration when transitioning to remote assessments.

For instance, Cioffi says that one may assume that site staff reading a subjective and seemingly benign measure over the phone, like a quality-of-life measure, would suffice for remote data assessment. “But you have to ask if that’s scientifically valid,” says Cioffi. “If the person reading that measure ad-libs the question or if they put unnecessary emphasis on part of the question, will that influence the answer of the patient?” Despite this potential issue, Cioffi says that there are several studies that validate the use of telephonic remote assessment of several endpoints across different therapeutic areas. In-depth structured interviews that are traditionally performed in the clinic, for example, have literature supporting the use of telephone administration.

“When moving to remote assessment, I would encourage people to look at the type of data that you’re collecting and understand if it’s going to be valid,” adds Cioffi. The other thing Cioffi recommends is using online video technology to remotely assess physical-related patient outcomes, such as fine motor control.

Cioffi adds that trial sponsors should ensure they are collecting enough validated safety and efficacy data when performing remote assessments. This will reduce the likelihood of having missing data at the end of the trial. “It’s very important to document what we do and why we fail to obtain certain measurements,” he says, “and that should be documented and clearly specified in the clinical study report if the limitation is actually imposed by the COVID-19 crisis that we’re going through.”

Sites and sponsors are moving toward reducing or eliminating site visits, adding virtual support staff and weighing the risk/benefit of continuing trials that may not have a direct benefit in the fight against COVID-19. All of these changes are resulting in many more protocol amendments than usual, experts say.

For trials that will continue, many sponsors are considering or actively seeking to change study protocols to allow for fewer onsite visits and more telemedicine or home visits, which can help reduce the risk of virus transmission. 

COVID-19 screening procedures mandated by the institution that is conducting the trial do not need to be reported as protocol amendments, the new FDA guidance said.

Following the FDA’s lead, on Friday the European Medicines Agency (EMA) issued a straight-to-final guidance that said sponsors in the EU should conduct risk assessments of all trial procedures in the face of the COVID-19 outbreak and also suggests they should hold off on initiating trials or adding participants to current trials.

The guidance says sponsors should consider such measures as:

• Conversion of physical visits into phone or video visits; 
• Postponement or complete cancellation of visits to ensure that only strictly necessary visits are performed at sites; 
• A temporary halt of the trial at some or all trial sites; 
• Transfer of participants to sites away from risk zones;
• Suspension or slowing down of recruitment of trial participants; 
• Extension of the duration of the trial; 
• Postponement of trials or activation of sites that have not yet been initiated; and
• Closing of sites.

The guidance also notes that some EU member states allow delivery of investigational medications directly to patients in a state of emergency.

In the U.S., the FDA emphasizes that trial participants must be kept informed of the nature and impact on their health of all changes made in relation to COVID-19.

Sponsors and investigators should document how restrictions related to COVID-19 led to study changes, the duration of changes, which trial participants were affected and in what way, and why specific data may be missing from case report forms. Sponsors also should address in their statistical analysis plans how protocol deviations will be handled.

The guidance said final clinical study reports should contain an explanation of contingency measures implemented to manage study conduct during disruption of the study, a list of all participants affected by unique subject number identifier and investigational site and a description of how the individual’s participation was altered. The impact of contingency measures on data analysis also should be addressed.

Changes made to protocols still need to be approved by IRBs, even if these changes need to be made rapidly. “Like most people in the IRB world, this issue is consuming a lot of our time and energy,” David Borasky, vice president of WCG Clinical’s IRB compliance, said during the webinar.

Consistent with the FDA’s new guidance, Borasky says that the IRB isn’t going to be a roadblock to making changes that are essential to maintaining research that is ethically appropriate and maximizes the safety of study participants, research teams and the general public. According to Borasky, research approved by the IRB before the COVID-19 outbreak will likely have to be re-approved if these protocol changes are made.

Changes made to a study protocol without IRB approval should still be submitted as soon as possible. The WCG IRBs expect changes to be reported to them within five days but understand that this may not always be feasible due to the constantly evolving circumstances associated with the crisis.

In addition to protocol changes, Suzanne Caruso, vice president of clinical solutions at WCG, says she is seeing dramatic shifts in the way trials are operating and communicating in response to the pandemic. “We are seeing departments that would typically see research patients close down and reopen to accommodate patients with COVID-19,” says Caruso. Additionally, Caruso says she is seeing tremendous reallocation of clinical trial nurses and other trial support staff to hospitals that care for patients with the virus. 

One of the increasing industry practices Caruso is hearing about right now involves moving toward adding virtual support staff to reduce contact between people. This is a somewhat considerable turnaround to how clinical trials traditionally operate. “Transparently, we do not have a lot of the industry working in the virtual space of clinical trials,” says Caruso. “The majority of trials ongoing are in the traditional model where the patient goes to the site.” As a result, transitioning to a virtual trial is a hot topic today.

“Where sponsors are beginning first is making sure that study coordinators have support virtually,” she says. “That means that sponsors are implementing additional virtual support staff that can take on the administrative functions for that clinical trial.” Administrative support tasks that can be handled virtually include scheduling/rescheduling visits as well as reaching out to study participants by email or phone to discuss whether scheduled onsite visits will be appropriate.

Caruso also says that she is seeing a lot of different strategies to support remote communications toward clinical trial teams. “There are now sponsors having webinars across all of their investigator sites,” she says. Short and concise daily emailed news reports about the study are also being sent out by sponsors to investigators and investigator staff. “These news reports are very, very helpful in letting study coordinators know what is ongoing,” says Caruso.

In addition, Caruso says that she is seeing a lot of industry partners, particularly in the European Union, who are employing a designated carrier to take an investigational product directly from a pharmacy to the patient, further minimizing the need for onsite visits. Borasky adds that trials that wish to ship investigational products directly to patients without them having to come into the site will need to get this approved by the IRB if this wasn’t included in the previously approved protocol.

Arthur Caplan, professor of bioethics and founding director of the division of medical ethics at NYU Langone Medical Center, says the kind of studies he believes need to end, at least temporarily, are observational studies, pragmatic trials, phase 1 studies and animal studies. “We have to cut those back because they’re not going to directly benefit in any imminent way for battling the virus,” he says. Studies that do not necessarily need to be stopped are those that are currently remote or those that don’t divert personnel who are needed in the clinical setting to care for patients with the viral infection. He also recommends continuing trials in which patients are clearly receiving a benefit from the drug under study.

Comments on the final guidance may be submitted to the agency at any time.

Read the FDA guidance here: https://bit.ly/2J4z92E. 

Read the EMA guidance at: https://bit.ly/2xRYlqN.