During the COVID-19 pandemic, medical oncologists continue to deliver the optimal care, which includes conducting clinical trials. The European Medicines Agency (EMA) has recently issued guidance on trial management during this period. Dr Stefan Zimmerman from the Lausanne University Hospital, Switzerland, shares his experience on how to balance maximal compliance with the protocol with the need to minimise exposure of trial participants to coronavirus.
Should oncology trials continue during the COVID-19 pandemic?
In my institution, where oncology research is skewed towards phase 1 or phase 1/2 clinical trials, we have implemented a recruitment hold for most studies. Their schedule is often intensive, with frequent safety visits that cannot be easily performed remotely, and many require support from radiology, interventional radiology, or pathology. Since these resources have been redirected, and many non-essential services suspended, conducting these trials is no longer feasible.
For example, all adoptive cell therapy trials using tumour-infiltrating lymphocytes have been interrupted, since they require an intensive lymphodepletion that leaves the patient immuno-suppressed up to several months, and therapy often requires intensive care, blood products, or aerosol-generating procedures that should be minimised.
What is the potential impact of stopping clinical trials on patients and on research?
For many patients, research represents hope, yet most understand that they are particularly vulnerable to COVID-19, are at increased risk of a severe course if they become infected, and that the balance between risk and benefit of some clinical trials may not be in favour of participation. This is a case-by-case shared decision. Oncology research is experiencing a hiatus at this time; trial participants have to be protected as much as we can, and this sometimes entails not enrolling them.
Should new trials be started during the pandemic or delayed?
We have not activated any new industry-sponsored clinical trial since the outbreak began. Of course, this does not apply to observational studies in relationship to COVID-19, the re-use of biological material or medical data, or clinical trials investigating pandemic-related interventions such as antiviral therapies. Feasibility and safety should be the key factors when deciding to activate a new study.
A few practical points we have considered: we have refrained from enrolling patients into combination immune checkpoint inhibitor studies, as we presume the incidence and severity of immune-related adverse events are much higher, and the use of steroids is a distinct risk factor should a COVID-19 infection occur. Also, we have systematically used the optional treatment pauses with subsequent rechallenge at progression offered in some protocols.
Is the COVID-19 situation likely to introduce more protocol deviations than normal for ongoing trials?
There are only so many deviations from the protocol you can accept before the scientific integrity of the trial is jeopardised, and this goes against the very interests of the participants, who have been exposed to a certain risk to gain knowledge about an agent or a disease; this becomes ethically unacceptable if the scientific questions can no longer be answered.
We are performing safety visits remotely whenever possible and using external labs. The occasional patient that has tested positive or is self-isolating will usually experience a lapse in therapy. We have not observed any tumour flare that could be attributed to a delay, although we ensure targeted therapies are dispensed via courier depending on the clinical situation.
How can the quality of trial data be ensured during the pandemic? How should data on COVID-19 positive participants be handled in the analysis?
Maximal compliance with the protocol has to be balanced with the need to minimise exposure of participants to coronavirus. These objectives may be at odds, and patient safety often prevails, at the expense of data quality. We are reducing disruption by continuing to document remote visits, annotating lab results performed outside of the study site, and following self-isolating patients through daily phone calls. Data on COVID-19 patients will be handled in various ways depending on the endpoint and the statistical plan. A lot of creativity and rigour are needed here a the same time. This may extend to outright patient replacements in some instances.
What is the need to initiate clinical trials on COVID and cancer?
Medical oncologists across the globe are scrambling to maintain adequate standards of care, and paradoxically, this sometimes means keeping patients away from the clinic. We are operating on the assumption that cancer patients are among the most vulnerable, yet the level of evidence is very low. Registries are urgently needed to obtain more granular information on associations of COVID-19 complications with certain clinical and pathological characteristics, and overlapping toxicities, for example with immune checkpoint inhibitors.