COVID-19 Operational Challenges Require New Risk Assessments
Sponsors and sites must reassess the risks of all their ongoing trials in the face of the COVID-19 pandemic, looking for factors that may increase the severity of already-identified risks and new, unanticipated risks presented by the virus.
“At a minimum … this is a time you need to do a reassessment,” according to Linda Sullivan, executive director of WCG Metrics Champion Consortium (MCC). “You need to go back and reassess the risk in the study in addition to adding questions.”
“There may be some things that weren’t considered high risk, [but] your whole risk profile might have changed,” Sullivan told participants in an online roundtable last week in which MCC members discussed operational challenges, including using local laboratories, remote information gathering and inevitable changes to protocols.
The assessment should consider risks at the study, site and patient levels, Sullivan said, and take into account the potential impact of missing data on the ability to draw conclusions from the trial.
Roundtable participants noted that some organizations are carrying out risk assessments at the enterprise and departmental levels, too.
The discussion among more than 100 clinical operations professionals focused on interpreting new guidance from various regulators and organizations when planning trial adjustments.
EMA guidance issued last week directs researchers to establish measures that prioritize data validity and patient safety, in addition to conducting reassessments as the pandemic develops, weighing trial risks created by COVID-19 against the predicted benefits of the investigational drug to patients and society.
The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) calls for reducing the number of patient visits and considering home delivery of trial drugs when possible.
MCC members wondered if moving to remote patient visits would be seen by regulators as a protocol deviation or even a protocol amendment. Both the EMA and the FDA have reassured sponsors and sites that an increase in protocol deviations is to be expected in the current situation and that they will not consider deviations directly related to COVID-19 as noncompliance with the protocol.
The FDA’s recent guidance on the impact of the pandemic on trials, issued March 18, urges sponsors to use more centralized monitoring practices when appropriate, and recently, the Association of Clinical Research Organizations called for increased centralized monitoring in response to the coronavirus (CenterWatch Weekly, March 23, 2020).
Sullivan also referred members to MCC’s own resources, including guidance on centralized monitoring, which already has been adopted in trials as an adaptation to proximity issues posed by COVID-19.
The group also discussed issues presented by using local laboratories in place of trial sites for critical testing, as both the FDA and EMA suggest.
The FDA recommends that when trial participants cannot make it to an investigational site for protocol-specified visits, other options should be considered, including local labs or imaging centers. In-person visits should be ruled necessary depending on patient safety. The EMA says it is acceptable to do lab, imaging or other diagnostic tests at local labs if they are certified to perform the tests routinely and testing can be done according to local restrictions on social distancing.
MCC members expressed concerns about the lack of standardization of tests across labs, concluding that safety assessments may be better suited for local labs than efficacy or exploratory ones. One participant posed that a lab’s viability will likely depend on the individual study,
patient population and therapeutic area, as well as its accreditation and possible use in conducting coronavirus testing. Local labs themselves may present an increased risk to patients if they routinely conduct COVID-19 testing, pointed out another participant.
The UK’s MHRA recommends sponsors consider discontinuing subjects who are at risk if they cannot complete integral evaluations or take critical mitigation steps. This could extend to an entire trial, although sponsors have the option of temporarily halting trials or pausing recruitment, the agency says.
The impact of trial changes on the informed consent procedure was another area of concern for roundtable participants, especially the need for reconsenting current trial patients without face-to-face contact. The EMA advises that any validated, secure electronic system for obtaining informed consent already in use in the trial would be an acceptable method as long as it is in compliance with member nations’ policies.
The FDA and EMA both allow emergency procedures without prior consent. The FDA advises sponsors and clinical investigators to tell their IRBs or ethics committees as soon as possible when they anticipate urgent changes to protocol or informed consent due to the public health emergency.
“Such changes to the protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants,” the FDA says “may be implemented without IRB approval or before filing an amendment to the IND or IDE, but are required to be reported afterward.” For protocol changes that will lead to amending data management and/or statistical analysis plans, sponsors should consult the applicable FDA review division, the agency says.
Roundtable participants shared suggestions on information that should be gathered about COVID-19. Recommendations included earliest date of exposure, the date of test result and mitigation strategies taking place locally, such as sheltering-in-place vs. social distancing. One participant recommended that MCC’s eCRF page in development include a hospitalization page to capture information about the virus, such as length of time in hospital.
The group also stressed the importance of documenting protocol deviations as they increase in prevalence alongside COVID-19 developments, and one participant suggested using “COVID-19” prefixes in their names for easy identification.
Other topics of discussion included how changes in data collection may impact the trial’s statistical analysis plan. For instance, does a mortality study need to consider the competing risk of death due to COVID-19?
Roundtable participants noted that COVID-19 infection could be a confounding factor in a clinical trial and debated whether all trials should test participants for the virus.
Ultimately, the group, concluded, trials should focus on the “quality-by-design” principles outlined in ICH E8(R1) to focus on collecting only data that is essential to the trial.
Read the FDA guidance here: https://bit.ly/2J4z92E.
Read the EMA guidance at: https://bit.ly/2xRYlqN.