Deciding When and How to Suspend Trials: Guidance from Industry Experts and the FDA
As the medical community shifts much of its focus — and its resources — to battling the ongoing COVID-19 pandemic, clinical trial sponsors and sites are left wondering what to do about ongoing drug and device studies unrelated to the coronavirus. Which studies should be paused and which should be allowed to continue? Could modifications to study protocols around data collection and patient visits strike a balance between maintaining both patient safety and the integrity of ongoing trials?
Answering these questions, experts agree, will require wrestling with a number of ethical and practical questions. A possible first step is to think about where a study is in terms of its “life span,” says Janet Wittes, founder and president of WCG Clinical’s Statistics Collaborative. A trial still in its infancy — either the design phase or the recruitment phase — can be easily halted. On the other end of the spectrum, a trial nearing its end — one in which the last patient visit has occurred and all that’s left is to address important queries and begin data analysis — can probably be ended rather quickly. At that point, it’s important to consider what queries actually need to be collected, Wittes says.
“Remember, the (research) centers are going to be extremely busy with COVID-19 patients and so some of the queries that aren’t really essential to analyzing the data or the interpretation of the study don’t need to be collected,” she advises. Focus instead on collecting important safety data and important efficacy data, especially data directly related to primary and secondary outcomes.
The most difficult decisions, Wittes says, will be for trials in between those life span extremes, where between 20 percent and 80 percent of study data still needs to be collected. For those trials, a number of factors should be considered, including whether they require patient visits and the status of the facility patients would need to visit. Is the patient population basically healthy, so that absent the study they likely wouldn’t be making visits to a hospital or clinic, like in phase 1 studies of new product safety? These studies are probably easy to halt, Wittes says. In other cases, study populations may already be hospital-bound, or they may be receiving study treatments that are having potentially life-saving or life-altering effects. In these cases, a strong argument could be made for continuing the study, particularly if protocol modifications can be made to mitigate COVID-19-related risk.
FDA Guidance on Clinical Trials During the Pandemic
The FDA recently released direct-to-final guidance to provide sponsors and sites with a window into the agency’s thinking about how to make trial adjustments during the ongoing COVID-19 outbreak. The agency acknowledged that protocol changes and deviations would likely be unavoidable for many studies and advised sponsors to carefully consider alternate approaches to data collection that could minimize face-to-face contact with study participants. Those approaches could include telemedicine visits,or the use of alternate facilities like local labs or imaging centers. The FDA also said trials should consider moving to centralized or remote monitoring rather than on-site monitoring.
In a question-and-answer section appended to the guidance, the agency emphasizes that patient safety is the most important consideration when deciding whether a given study should be suspended or continued. The FDA recommended a number of assessments sponsors and sites can make to help reach that decision, including:
- Assessing whether limitations created by the pandemic on protocol implementation pose new safety risks to participants and whether the risk can be practically mitigated by amending study processes and/or procedures;
- Weighing whether the clinical investigator/sub-investigators will be continually available to oversee the trial and assess/handle safety issues that arise;
- Determining if there will be enough trial support staff on hand and adequate equipment and materials available to them;
- Considering whether clinical investigator sites will remain open to participants for required in-person assessments or whether the investigator has the ability to give required in-person assessments at an alternative location(s) or whether the assessments can be done virtually;
- Evaluating the continued availability of trial supplies and continued operations of vendors, especially related to the investigational product and supplies essential to maintaining safety monitoring and other key trial procedures;
- Assessing if IRB, Independent Ethics Committee (IEC) and Data Monitoring Committee staff will continue to operate, and if there will be adequate communication with them to support trial needs; and
- Weighing public health measures that may be in place by federal and state authorities for the coronavirus, and if they could impact the trial.
David Forster, WCG Clinical’s chief compliance officer, says it’s important for there to be ongoing dialogue between sponsors, sites and institutional review boards (IRBs). The FDA guidance supports increased IRB flexibility, he notes, allowing sponsors to bundle amendments and institute changes to deal with apparent immediate hazards or threats to patient safety. But it’s not entirely clear how sponsors should streamline IRB reporting.
“At this point, I believe most IRBs will be satisfied with receiving notices of protocol deviations or changes in research that are made to eliminate immediate hazards in any format, such as email or letter,” he said. “The IRB’s main concern at this point is to ensure that subject and research staff safety is enhanced as much as possible given the pandemic.”
Making Changes to Data Collection
Once a decision has been made to continue a study, the next step is to think about how it might be modified to minimize patient risk while maintaining the trial’s data integrity. This could include a range of strategies, from rethinking what data needs to be collected to modifying the means of data collection. Home visits, telemedicine or other uses of technology could minimize the exposure of study participants to the hospital or clinic, as well as minimizing contact between participants and study staff.
“One way to reduce risk is to reduce the number of required visits, and one way to do that is by collecting less data or reducing the number of data points,” says Jonathan Seltzer, chief scientific officer for WCG Clinical. He advises sponsors to think through which data points are actually necessary for the integrity of a study, and which could be jettisoned. Among necessary data points would be:
- Significant adverse events;
- Adverse events that are of special interest to the study, as outlined in the study protocol; and
- Adverse events of special interest because they’re specifically related to COVID-19.
Data that may be unnecessary, or could at least be collected less frequently, includes vital signs and standard lab data. “We generally take heart rate, blood pressure, respiratory rate, standard laboratory data,” Seltzer says. “But do we actually need to get them?” For data that is required, he suggests, trial sponsors may consider sending patients to a local lab, rather than a hospital or clinic that may be focusing its attention on COVID-19 cases.
Necessary data will of course be study-specific, he notes. For a cardiology trial, for instance, it may be impossible for patients to replicate a full ECG from home. However, an Apple watch or similar product could be used to effectively monitor for arrhythmia. Likewise, a study may have X-rays on the schedule, but those X-rays may not be absolutely necessary to the study’s endpoint.
“At the end of the day, if you can’t use the data that you get from the trial, then we’ve wasted everyone’s time,” Seltzer says. “So we want to figure out how we can keep the high integrity of an ongoing trial, while maybe taking our foot off the gas a little in terms of how much data we’re collecting.”
There’s a tendency in study design to default to in-person visits, but certain data can be reliably collected remotely, says Michael Cioffi, senior vice president of clinical solutions and strategic partnerships at WCG Clinical. Cioffi acknowledges that there may be pitfalls with collecting data through phone calls. What if, for instance, a site staff member is taking quality-of-life measures over the phone, and they ad-lib a question, or put unnecessary emphasis on one part of the question, in a way that influences the patient’s answer? However, he notes that several studies have validated the use of telephonic assessment of various endpoints across a wide variety of therapeutic areas. There’s robust literature, for instance, that supports performing in-depth, structured interviews over the phone.
Cioffi also encourages sites and sponsors to think about the kinds of data they can collect through video technologies like Skype or Zoom. These could include remote assessments of physical patient outcomes such fine motor control.
Managing a Study’s Statistical Analysis Plan
Any clinical or operational changes to a study — particularly those affecting the volume or type of data collected — will have an impact on the study’s statistical analysis plan (SAP). It’s crucial, Wittes says, that the people making operational or clinical decisions communicate meaningfully with the statisticians charged with analyzing study data. “Very often there’s this unfortunate separation between operations on the one hand and statisticians on the other,” she says.
The first step is to carefully read through the existing SAP — not just the statisticians, but everyone involved in the study’s management, including the clinical team, the operational team and staff members managing the trial’s databases. “Everyone involved in the trial needs to understand what’s in that statistical plan,” Wittes says. “Everyone needs to understand how operational changes arising from COVID-19 will affect that plan.”
As an example, Wittes mentions an ongoing study she’s been involved in, where patients were scheduled to come in at week 20, week 22 and week 24, which would be the final patient visit. Due to COVID, a decision was made to keep only that final visit and then close out the study. That meant the SAP had to change, to define weeks 20, 22 and 24 as one endpoint, labeled as “24.” “So that’s an example of the interplay between the operational changes and the statistical changes,” she says.
Any amendments to the SAP should be explained, in writing, so they don’t later appear arbitrary to regulators. The study’s sensitivity analysis also needs to be thoughtfully redesigned, particularly to account for studies that will now have a pre-COVID portion, a during-COVID portion and possibly even a post-COVID portion.
Sponsors also will need to modify their plans for missing data. Those changes should include modifying study databases so that missing data can be pinned to operational issues related to COVID-19, when appropriate. For instance, say a visit originally scheduled to be conducted in-person is instead conducted via phone, and some of the originally scheduled procedures cannot be conducted — a particular eye exam, perhaps. That missing piece needs to be properly categorized, Seltzer says. It wouldn’t be fair to call it a missing visit, and it’s not the same scenario as a patient who comes in for the visit but refuses that particular exam. “So I think it’s important to modify the database in such a way that you can identify what part of the missing data was operational, because of COVID-19, and what part was volitional,” Seltzer says. “Because in analyzing that data, one kind of ‘missing’ can be informative, but the other is an act of God and therefore not informative.”
Wittes emphasizes that these categorizations are important because statisticians tend to be conservative in their analysis. When it comes to missing data, she says, the assumption is usually that it’s missing for a reason related to the patient or their condition — that the patient missed a visit because they didn’t feel well or they were experiencing an adverse event. So if that’s not the case, the actual reason should be documented.
The Role of Data Monitoring Committees
When changes need to be made to a study’s protocols, there are three primary groups that may need to be involved, Seltzer says. The first is the institution where the study is being conducted. “They may recommend that it’s unsafe to continue or that they don’t have the capacity to support clinical trials right now,” he says. The second is the study sponsor, obviously, since they’re the “owner” of the study’s protocols and would need to spearhead any changes. The third group that could play a role is a data monitoring committee (DMC) or data safety monitoring board (DSMB). Not every trial will have one; Seltzer says about 25 percent of industry-sponsored studies do, though the numbers are much higher for trials sponsored by government or universities.
Recent FDA guidance on COVID-related clinical trial modifications suggests that sponsors can consult with a DMC or DSMB on study modifications though sponsors also need to be careful about the types of questions they pose to a committee. In many cases, such as a phase 3 drug trial, the DMC or DSMB will be unblinded, so committee members may already have viewed efficacy data. “It may be tempting to go to them and say, ‘Well, what should we do with this trial?’” Wittes says. “But an open-ended question like that could affect the validity of the trial.”
If a trial doesn’t currently have a DMC or DSMB, it’s still possible to add one. It’s also possible, Wittes says, to expand the role of an existing DMC or DSMB. The committee could be useful, for instance, in helping to define which adverse events are of special interest for a particular study. A committee could also help perform, with sponsor guidance, a new interim analysis of an ongoing study. If a DMC or DSMB has the relevant expertise, it could look for evidence of either futility or benefit to help make a decision about whether a given study should continue.
The European Medicines Agency (EMA) has actually released special guidance on the role of DMCs during COVID-19, Seltzer notes. According to the EMA, a DMC could recommend:
- How to restart usual trial operations and additional measures to take when completing a trial after the pandemic (e.g., validation of outcomes that were measured differently due to COVID-19);
- The need to adjust the trial sample size and additional analyses (to be included in the SAP) to investigate the impact of the three trial phases (pre-COVID, during-COVID and post-COVID) to understand the treatment effect as estimated in the trial; and
- Proposals to deal with any potential sources of bias, such as missing values, newly identified intercurrent events or other unforeseen but required changes to trial elements.
During COVID-19, it’s especially important that a DMC or DSMB be prepared to make rapid decisions, Seltzer adds. If the committee sees study data that look especially good, for instance, it may be asked to make a decision on ending the study early, rather than continuing to collect data that is, in a sense, only gilding the lily. On the flip side, a committee may be asked to make a decision on halting a study if the data looks like they are trending toward futility.
“So I think if you’re considering putting together one of these committees right now, you want to make sure the members understand that responsibility and are willing to take it on,” he says.
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