Changes to Study Visits and Assessments During COVID-19: Subject Safety Considerations
April 9, 2020
The COVID-19 pandemic has understandably generated a surge of concern among clinical researchers about how best to minimize the risk to study subjects of exposure to COVID-19 while also preserving study integrity and a favorable risk-benefit of study participation for subjects. In general, research principles don’t change because the world is going through a public health crisis, and the principles of Good Clinical Practice, risk-benefit, subject safety, and ethics remain as fundamental priorities of clinical research. However, we can shed some light on specific topics that might be considered during this time, which are also approached in the recent April 2020 update to the FDA Guidance on Conduct of Clinical Trials of Medical Products during the Covid-19 Pandemic.
It is critical during the COVID-19 pandemic that sponsors consider each clinical trial circumstance specifically, including potential unique or increased risks associated with continued study conduct, taking into consideration the nature of the investigational product (IP), the appropriateness and feasibility of continued or changed safety monitoring, supply chain limitations, and the nature of the disease under study. Any changes made to the study plans should be communicated to subjects and study institutional review boards (IRBs) as soon as possible and documented appropriately via protocol amendments and the clinical study report.
Some common questions related to study conduct during the crisis include the following:
• Should ongoing study recruitment be halted? Some of the considerations that should be included in this decision include the ability of site and site staff to remain available throughout the intended duration of the trial; the operational status of study-associated vendors, supply providers, and information technology systems; and the ongoing availability of Data Monitoring Committee members, when applicable. Product specific considerations may be necessary as well, depending on the potential mechanism of action of the product in development, and whether it has a possible risk of increasing COVID-19 infection risk or seriousness to subjects.
• What if enrolled subjects cannot travel to the study site for protocol specified visits? Alternative methods for safety assessments, including phone visits, virtual visits, or alternative locations should be considered when necessary and feasible. We encourage study sites to have open discussions about the potential impact of study visit changes with their IRBs and study sponsors before any changes are implemented. When alternative methods to complete study assessments are inadequate to maintain a favorable study risk-benefit and/or study integrity, the study may need to be modified to achieve this or halted if this is not possible.
• In what ways can we reduce risk of subject infection while maintaining access to IP? Sponsors should consider whether home assessments and delivery of IP is feasible for their studies. The latter may require special shipment considerations if warranted by IP storage and handling requirements. It is important to note that any changes in IP distribution should follow existing regulatory requirements for IP accountability and should be fully documented.
While assuring the safety of trial participants is paramount and deviations from a clinical study protocol to achieve this are allowed in acute emergency situations, during this ongoing crisis it remains essential to maintain compliance with good clinical practice (GCP) and ethical standards of research conduct, and to minimize risks to trial integrity. In other words, it is neither necessary nor appropriate to violate research standards or guidelines during this crisis. In order to continue a clinical study – whether in its original or modified form – the study must still have a favorable risk benefit for the subjects, the assessment of which includes three important components:
i) The risks and benefits of the study intervention during a viral pandemic,
ii) the ability to adequately monitor and assure subject safety during the trial, and
iii) the ability to continue to gather meaningful and reasonably complete study data, since without this an essential component of ethical research conduct cannot be met.
In many cases, perhaps a majority, we believe that these components can be met and the clinical research can be safely and ethically continued. Sponsors and investigators must, however, recognize that in cases where necessary study modifications are impractical or inadequate to achieve these required components, the study may need to halted or delayed until such time that external conditions sufficiently improve to allow the study to safely and ethically resume.
Monica Frazier, PhD, RAC, Research Scientist, leads and contributes to multiple integrated product development programs at Rho, where she has experience in management of regulatory submissions at multiple stages of product development (INDs, NDAs, etc.) as well as in development of clinical documents to support clinical studies and regulatory submissions. She has over fourteen years of research; scientific and regulatory writing; and project management experience. Her experience includes leading and managing scientific authoring and editing teams, as well as preparing modules of regulatory submissions; briefing packages to support regulatory meetings; clinical study protocols; and clinical study reports.
Dr. Jamison Chang, Medical Officer, is a board-certified internist with over 15 years of clinical experience with a broad range of disease entities in both the ambulatory and hospital settings. After completing his residency and chief residency at UNC Chapel Hill, he obtained additional training in nephrology as well as a master’s degree in clinical research (MS-CR). These experiences allow Dr. Chang to meld clinical pragmatism with scientific rigor to help plan and conduct high quality clinical trials. As a medical officer at Rho, Dr. Chang’s responsibilities include pharmacovigilance and advising project teams on the clinical and scientific issues to ensure safe and well-executed clinical trials.
Jack Modell, Vice President and Senior Medical Officer, is a board-certified psychiatrist with over 35 years of experience in clinical research, including 20 years conducting trials, teaching, and providing patient care in academic medicine, and 15 additional years of experience in clinical drug development (proof of concept through market support), medical affairs, successful NDA filings, medical governance, drug safety, compliance, and management within the pharmaceutical and CRO industries. Jack has authored over 50 peer-reviewed publications across numerous medical specialties and has lead several successful development programs in the neurosciences. Jack is a key opinion leader in the neurosciences and is nationally known for leading the first successful development of preventative pharmacotherapy for the depressive episodes of seasonal affective disorder.