Clinical Trials in the Age of Pandemics

Clinical trials play a unique role in the treatment of cancer patients. While only a small percentage of patients actually enter studies, enrollment onto a trial is considered a “standard of care” for virtually all patients with advanced or locally advanced cancer. Even for diseases where therapeutics have achieved high cure rates there are trials evaluating strategies to minimize duration and toxicity of treatment.

The effort required to formulate, activate, accrue and analyze trials is considerable; even small trials require a sizable effort. Large, definitive trials may consume hundreds of person-hours, span the globe and cost in excess of $100 million. Prior to the current pandemic, there was recognition that the existing system imposed an undue regulatory and administrative burden on investigators and had arbitrary entry criteria that restricted enrollment.^1.2

The COVID-19 pandemic has disrupted all aspects of social, work, and economic life throughout the world.^{3 4}While completion of clinical trials in cancer is certainly not the most pressing issue at this time, it is of substantial importance to patients, physicians and sponsors. The substantial morbidity and mortality for patients with cancer is not going to go away. Furthermore, cancer patients with COVID-19 infection are at high risk for adverse outcomes.⁵ A marked decline in screening and accrual to trials within the National Clinical Trials Network has been noted.⁶ Regulations governing clinical trials allow for the occurrence of study modifications to be implemented prior to IRB approval without adverse action only when it is necessary to eliminate apparent immediate hazards to the subject.⁷ This allows investigators to modify protocol-required visits or make other protocol changes if it is in the best interests of the subject. These deviations must be reported to the IRB of record within five days.

Agencies including the National Cancer Institute and the Food and Drug Administration have issued guidance regarding management of patients during the pandemic.^8.9.10 As with the above, modifications can be made in the interest of patient safety without adverse action. Additionally, if modifications to protocol assessment schedules can be proactively identified to minimize risk to subjects, these can be submitted to the IRB of record as a planned deviation prior to implementation, with short turnaround times from submission to IRB approval to optimize subjects’ outcomes. The NCI guidance contains procedures for forwarding some investigational agents directly to patients.

However, the guidance is non-binding on industry, may result in further confusion and critically, does not address the next disruptive event. The NCI guidance applies only to NCI sponsored research while the FDA guidance can be interpreted variably by sponsors. Critically, substantial burden is placed on investigators and their institutions in terms of absorbing the risk of being deemed non-compliant with the IRB- and sponsor-approved protocol. Such risk could include significant financial liability if sponsors penalize institutions for such “non-compliance” as well as for the potential of adverse action by the FDA (e.g. issuance of a form 483).

It is important to recognize that, regardless of when the current pandemic ends, similar disruptive events from disease and/or natural or manmade disasters will inevitably occur in the future. Planning for such events is a necessity. The following represents a series of specific proposals for emergency trial guidelines that we hope will initiate discussions and policies in anticipation of future disruptive events and to mitigate their impact on clinical research efforts in oncology.

1. All studies should have a clear set of contingencies regarding the ability to delegate study procedures to other practitioners outside of the investigator team or through remote means as part of the initial protocol. Guidelines for activating these contingencies should be delineated within the protocol document and be consistent across industry sponsors. This will eliminate the need for amendments requiring IRB approvals or for the generation of study deviation reports etc.

2. To activate contingencies in the setting of a disruptive event, site investigators should ascertain that continuing individual trial participants on study therapy is in the patient’s best interest and document that contingency plan activation is being done for the safety and best interest of the participants.

3. In circumstances where patients are traveling to investigative sites or where it is considered in the best interest of the patient to avoid the investigative site, contingency plans should include a clear mechanism and oversight plan for “deputizing” local health care professionals to perform exams, toxicity assessments etc. on study participants. This could include permitting a participant’s referring oncology or primary care provider to conduct clinical assessments. Many assessment visits require straightforward history and exam. It would not be difficult to have local health care providers complete basic paperwork (e.g. disclosure, FDA form 1572, clinical research training) remotely and review an activations slide set to acquaint themselves with basic information regarding a specific trial. It is routine at our center for the slides from site initiation visits to be distributed to all investigators, including those who may not have been present at the actual meeting. A signed document indicating review of these slides, particularly those dealing with assessment of toxicity, could be submitted remotely. Site investigators with a large network of outside referring physicians should engage participants’ local health care teams early in treatment to ensure a smooth continuation of assessments and care, should the need arise.

   An alternative to the above approach is the use of telehealth visits for many of the “routine” visits that are mandated as part of trials. We have employed this approach for many studies during the current pandemic. While such visits do not allow for physical examination assessment, they are appropriate for determining symptomatic toxicities.¹¹

4. Results for routine laboratory studies (e.g. complete blood counts, chemistries etc.) from sources other than the study institution should be accepted as source data, provided those labs are CLIA certified. In addition, if possible, such labs should also be able to draw and ship study-related pharmacokinetic and other samples. Third party home phlebotomy and visiting nurse services could be engaged to allow standard sample collection for needed studies without participants having to travel to distant study centers.

5. Provision of drug, directly to participants for oral agents or oral and parenteral agents to suitable practitioners (e.g. community oncologists), should be allowed. Procedures for drug delivery through commercial carriers should be developed in the setting of travel restrictions. It is very common for community physicians to participate in some aspects of research through the National Clinical Trials Network mechanism or through industry trials. They are therefore frequently familiar with the basic tenets of drug accountability. Again, this could be accomplished through engagement with participants’ local oncology providers.

6. Operating procedures for obtaining participants’ informed consent remotely for protocol amendments describing new risks of procedures requiring re-consent should be outlined. These may include the use of video platforms, audio recordings, and other electronic media to send and receive verbal and written informed consent for protocol changes, but would not be applicable to new participant consents to initiate study treatment.

7. Mechanisms and procedures for urgent transfers of care from one study center to another, should be outlined. Such transfers should allow for participant identification numbers to travel with the participant to the new site to allow for continuation of care while the formal transfer of care and data is accomplished. This will allow study-related data to be collected and assigned to the correct participant while minimizing interruptions in treatment cycles. The transfer of care should be able to be accomplished regardless of the status of data submission or query resolution at the initiating site.

8. Mechanisms to allow for remote monitoring of trials should be in place prior to activation. This would include methods of accessing electronic medical records and other relevant data. Procedures for discussions with investigators and study staff by telephone or other methods not requiring direct contact should be delineated.

9. Statistical methods to evaluate the results of trials that use such contingency plans should be part of the initial study document. For example, sensitivity analyses could be planned to explore whether the cohort of participants treated under emergency contingency guidelines may bias trial conclusions. Furthermore, it is quite possible that patients who are participating in trials may succumb or become non-evaluable due to the epidemic disease or other event. The statistical plan should describe if these patients will be replaced, supplemented or excluded.

The current era of oncology clinical trials holds immense promise for effective therapies to drive continued reductions in cancer-related morbidity and mortality. The COVID-19 pandemic has disrupted clinical research of promising therapies in ways no one had previously considered. As investigators, we do not want our progress derailed by failure to plan for inevitable unforeseen disasters, natural or manmade. Contingency approaches such as those detailed above should be put in place as soon as possible for existing trials and incorporated as a matter of course into future trials prior to activation. It is already clear that clinical trials in oncology can proceed, even in the most severely impacted areas. The Phase I unit at the Department of the European Institute of Oncology in Milan has demonstrated that measures such as those described above can allow for the continued accrual to even the most complex studies.¹² Planning for the unforeseen now ensures that we will be able to continue to advance the field of oncology while simultaneously confronting other challenges to human health in the future.