By Laurie Halloran, CEO and Chairwoman of the Board, Halloran Consulting Group, Inc.
Life science companies across the world are scrambling to mitigate the impacts of COVID-19 on their clinical studies and business operations, and there are no clear-cut answers at this time, nor a one-size-fits-all solution. But what we do know is that we are all in this together and that this is another challenge that the biotech industry was built for — to take an unknown medical problem with no clear solution and try to find the best path forward. Sharing the knowledge we gather can help ensure that patients who are most in need have a contingency plan in place to continue receiving therapies, while keeping patients enrolled in studies safe.
We are all faced with a myriad of issues, such as patients’ inability to attend site visits to receive treatments and/or follow-up visits, delayed investigational product shipments, questions about study drug stability due to delayed shipments, site inspectors and clinical study representatives inability to visit sites, patients declining to attend study visits, and sites suspending research activities altogether.
On March 20, Halloran Consulting held the first in a series of Virtual Town Halls to openly discuss some of these COVID-19-challenges. It is clear that everyone is looking for answers and turning to their industry colleagues for advice and knowledge sharing. This article shares some of the insights gathered during that event. (For my previous articles on the impact of COVID-19, see “8 Significant Risks COVID-19 Poses To Clinical Trials — And How To Mitigate Them” and “Assessing The Impact Of COVID-19 On Regulatory Interactions, Inspections, & Audits.”)
Overcoming Social Distancing Hurdles
The immediate impact of the pandemic is felt in everything that requires in-person meetings (e.g., site initiation visits, monitoring visits, regulatory inspection, audits, etc.). Many companies are looking to immediately implement remote monitoring procedures, but because such procedures have been unevenly employed in the U.S. to date, sponsors lack the infrastructure and established processes to transition quickly. The situation is worse in the EU, where GDPR requirements make remote monitoring nearly impossible. In the U.S., sponsors are trying to transition to risk-based, centralized monitoring. Globally, all sponsors and investigators need to be aware of specific regulations and guidance in place at the national and institutional level, which should be consulted before making any clinical trial changes.
Data, once entered into electronic systems, allow sponsors the opportunity to clean and analyze it in real-time through review of listings and blinded patient profiles generated from the electronic data capture (EDC) system. Remote monitoring is a little more difficult if a sponsor does not have prior remote experience, but taking a risk-based approach and focusing on the critical safety data from the sites and subjects is a good first step. Conducting source document verification remotely is a challenge, but some sponsors have found success by setting up secure email feeds to receive data. Any changes to monitoring strategy must be documented, ideally in the monitoring plan.
Audits of sites and vendors are also impacted by the lack of accessibility to investigational and vendor sites. Again, a risk-based approach should be employed. Alternative methods such as questionnaires and remote/virtual audits have been successful. Web-based file share platforms such as Box can facilitate review of documentation and SOPs, and read-only access can be provisioned to the necessary people for finite periods.
Since patients have been unable to get to investigational sites, some sponsors have been able to replace site visits with telemedicine visits. While an option, these visits do not facilitate sample collection or diagnostic procedures requiring special equipment, ultimately necessitating documentation to justify protocol deviations due to the pandemic. Additionally, sponsors are experiencing long lead times in getting telemedicine visits implemented as site resources are constrained. Home health visits are also an option that has been discussed; however, many patients are uncomfortable with the potential exposure that would come with outsiders visiting their homes. Additionally, the growing demand on home health services may limit capacity as the number of studies utilizing their resources expand exponentially.
Ensure that regulatory authorities, institutional review boards (IRBs), and study participants are aware of any changes to study protocol and procedures. Participants must also be informed of the changes and re-consented. Many sites are conducting virtual video consent or using e-consent procedures so the patient does not have to come to the site. Depending on the changes to the study protocol and/or procedures, sites and patients may need to be trained on these new protocol procedures or study tools. The impact of these changes on study site budgets will need to be calculated, and budgets may need to be renegotiated with the sites. Close coordination is required across many different functions. During the Town Hall, several companies brought up the importance of staying connected with their project teams regularly. Some have initiated 30-minute video team huddles each day to review changes, new risks, and effects. We cannot underestimate the importance of our teams, and constant and close communication with project teams is required to keep things moving forward and maintain morale. This is certainly a topic that deserves its own focused discussion!
The pandemic has forced companies to challenge traditional study conduct and to implement some concepts that have been deferred over time, such as remote-based monitoring, centralized risk-based monitoring, data analytics tools, e-consent, ePRO tools, telehealth and home visit optionality, and protocol simplification/streamlining. Fortunately, many companies are taking this opportunity to innovate, adopt new technology, and to reflect on what is necessary to achieve the primary objectives of their studies.
Risk (Re)Assessment In The Age Of COVID-19
All decisions to adjust clinical trial conduct should be based on a risk assessment by the sponsor, in collaboration with the investigators as it pertains to each participant. The sponsor must implement measures that prioritize patient safety and the integrity of the trial data. In the case of a conflict, patient safety should always prevail. The risk assessment should be documented on an ongoing basis and should be reassessed as the situation develops. Each reassessment should also be documented for future inspection readiness, establishing a record of the full story of the changes and the rationale behind them.
COVID-19 is forcing sponsors to appropriately assess and document the impact of the pandemic on their operations, safety, and data integrity, as well as the measures being taken to address these risks and issues. In some cases, this risk assessment is being done at the program level and even down to the subject level, versus just at the study level, since the risks and issues are similar across the board. Quality tolerance limits (QTLs) and key risk indicators (KRIs) are being newly established or adjusted to appropriately assess the risk COVID-19 will have on studies.
While most sponsors have employed some type of risk assessment in their studies as a matter of routine, many are relying on their vendors’ risk assessments, which is proving challenging as CROs are also overwhelmed in their efforts to mitigate the crisis. Regardless of who initiates a risk assessment, it is important to include vendors in this process. Assess how well each vendor’s risk management infrastructure handles such dramatic shifts in their operations. This must be an ongoing and iterative process as new issues become known and new risks are identified. As the entire health system adjusts to this crisis, each adaptive measure taken must be documented and justified.
Preparing For Future Complications
There will likely be events related to COVID-19 infection or exposure that could have serious effects on the overall benefit-risk of the trial. The sponsor and investigator may need to take immediate action to protect subjects against hazards. These urgent safety measures may be taken without prior notification, but they need to be reported to regulatory authorities, IRBs, and ethics committees (ECs) as soon as feasible, and should be documented as part of the study conduct.
For some sites, investigators and other study staff may be conscripted to provide healthcare to patients infected by COVID-19, and therefore they will be unable to fulfill clinical trial duties. Some of our Town Hall participants suggested qualifying new sub-investigators to see patients for their study visits. While we have received isolated reports of U.S.-based sites suspending all clinical study activities, some countries have imposed more broad restrictions towards continued clinical trial activity (e.g., Poland).
As the various constraints in patient visits and procedures extend over a longer period, new case report forms may need to be created or revised to collect COVID-19-related data. Other potential issues arise for longer-term considerations. For example, slowed or suspended enrollment of new study patients will prolong the study, driving budget increases and timeline delays. Inability to conduct critical procedures supporting primary endpoints or key secondary endpoints will impact data analysis. Early discontinuation of patients may require replacement of patients to preserve underlying statistical assumptions.
The clinical study report will need a separate section to address any impact of COVID-19 on the study procedures and analysis, as well as what actions were taken in response. The statistical analysis will likely need to be revised to take into account the impact of COVID-19 on the endpoints of the study. It is important to keep an open dialogue about these protocol changes with regulatory agencies as well as the ECs and IRBs to ensure there are no issues when the sites are ready to resume enrollment.
We are looking to companies running clinical studies in Asia for answers about how long we will need to rely on adaptive measures in response to COVID-19. Town Hall participants running studies in China reported that they are now seeing some sites being reopened, allowing clinical trial subjects to be seen And monitors to conduct monitoring visits. Disruption to clinical trials in China began in early January 2020, so a resumption in some clinical trials there in mid-March suggests we may expect a similar timeframe here in the U.S. — approximately two months before study subjects can be seen freely for hospital visits.
The current effects of the COVID-19 pandemic will likely leave a larger set of long-lasting challenges. As we move out of this phase, we need to have strong and thorough documented evidence of every action taken to mitigate the risk to subjects and to the integrity of data. These changes have implications not only on protocols and informed consents, but also on oversight plans, monitoring plans, statistical analysis plans, data management plans, and many other study-related documents that will need to be prepared for future inspections. One recommendation from our Town Hall was to begin documenting these clinical study changes in a storyboard for when inspections resume, or as preparation for remote inspections.
Although regulatory agencies have suspended on-site regulatory inspections, remote inspections are a real possibility. A successful remote inspection requires the agency to have access to all the clinical study data and trial master file (TMF). In such cases, sponsors must establish procedures to allow inspectors to train on necessary tools and receive access to the data and documents in real-time.
Regulators have released and updated several COVID-19 clinical trial guidance documents. These should be referred to as you navigate these mitigations.
If you would like to be included in future Halloran Virtual Town Halls on COVID-19, please send an email request to firstname.lastname@example.org.
About The Author:
Laurie Halloran, BSN, MS, founded Halloran Consulting Group in 1998. Her time as a pediatric ICU nurse had inspired her to start a company that helps move new therapies through FDA processes to get them into the hands of patients desperately in need. Halloran has been named 2018 Women’s Business Enterprise Star by the Women's Business Enterprise National Council (WBENC) and has won a 2017 Enterprising Women of the Year Award from Enterprising Women magazine. Halloran Consulting Group was also named an Inc. 5000 Fastest Growing Company for the past three years in a row.