by Manasi Vaidya in New York and Reynald Castaneda in London.
The ongoing Covid-19 pandemic is extensively impacting clinical trials irrespective of indication and not just in terms of recruitment and immediate patient care, but is also likely to affect data collection and analysis in the months to come. The worldwide pandemic of Covid-19, which is caused by the novel SARS-CoV-2 virus, started in late 2019 and has since spread all over the globe with more than 219,094 confirmed cases and 8,959 deaths, as per data from the World Health Organization.
Several oncologists, investigators and specialists in other indications from the US, Europe and Australia talked about Covid-19 preparedness programmes at their clinical centres taking up their primary focus, and the multiple ways care for patients on or outside of clinical trials has been altered. Trial recruitment is likely to slow down due to curtailed patient visits to the hospital as per guidelines. Reallocated resources for clinical trial management will mean Phase I healthy volunteer recruitment will likely be hit significantly.
While several oncologists are sharing tips on managing immunotherapy and chemotherapy schedules through community newsletters and social media, physicians this news service spoke to also mentioned changes to follow-up and screening schedules for trials. The National Institutes of Health (NIH) and the FDA also issued guidelines for centres running clinical trials.
Moreover, experts also already expect a long-term impact on data collection for ongoing studies, and the lack of widespread Covid-19 testing for patients possibly confounding eventual results.
Trial enrollment expected to slow down
COVID-19 preparedness programs are indeed taking precedence over ‘non-urgent additional nonclinical activities’, said a British oncologist. The healthcare system has significantly slowed down, with resources diverted to quell the pandemic, which is stretching existing capacity, said Dr Ronald DePinho, professor, Department of Cancer Biology, MD Anderson Cancer Center, Houston. An inflammatory bowel disease physician in Norway called it a ‘crisis situation’ in public hospitals. Dr Leonard Saltz, medical oncologist, Memorial Sloan Kettering Cancer Center, New York, also mentioned that clinicians like himself are working from home four days a week to minimize contact. Five employees and three patients at the hospital have been diagnosed with Covid-19, as per a 17 March news report citing internal communication.
Saltz expected a three-month delay on trial operations to be the best-case scenario, but even after that, it is unclear what will happen since there is no precedent. While the NIH and FDA issued guidelines earlier this week (on March 16 and 18, respectively), Dr Harry Bear, chair, Division of Surgical Oncology at Virginia Commonwealth University, told this news service that guidelines for running clinical trials, including strategies to handle follow-up visits, are also being discussed by the US-based investigator-led consortium of NRG Oncology.
While pharma-funded studies are not bound by the NIH guidelines, a lot of these trials are conducted at research centres that have a mix of private and public spending, said Joel Wallace, IP partner, Schiff Hardin, Chicago. These centres would have to become compliant with the NIH guidelines for NIH-funded studies, so this may affect pharma-sponsored trials as well, he added. When it comes to trial enrolment since patients are not coming in for regular checkups, screening for trial participation will be affected, said Wallace. Moreover, Dr Sami Hoque, a consultant gastroenterologist at Barts Health NHS Trust at Whipps Cross University Hospital, London, said he has stopped screening patients for trials, as other activities take precedence. The impact on enrollment will depend on the nature of the study, so for example, a trial that involves multiple follow-ups will likely see a negative impact even at the enrollment stage, said a US-based breast cancer oncologist.
Phase I safety studies that recruit healthy volunteers could particularly be held up, said Wallace. Research organizations or divisions at hospitals that routinely recruit volunteers and run labwork are being told to pause operations to devote resources to Covid-19, which in addition to the increased difficulty in getting volunteers could hold up Phase I trials, he added.
However, Dr Philip Philip, medical oncologist, Karmanos Cancer Institute, Detroit, Michigan, said while there could be an impact on recruitment, he did not anticipate US clinical trials to suffer excessively due to the pandemic. While routine check-ups will reduce, it could potentially free up more time to tackle other elements of the clinical trial to help compensate.
Patient follow-up and data analysis also not immune to COVID-19
The Covid-19 pandemic is bound to impact clinical trials beyond just erecting enrollment hurdles, experts noted, pointing to challenges from patient monitoring through to data analyses. The NRG website currently encourages investigators to explore alternative methods for obtaining data, such as telehealth visits but adds that member sites will not be penalized for data delinquencies or protocol noncompliance during this time period.
NIH’s guidelines include limiting study visits to those needed for safety check-ups or if they coincide with clinical care and also encourages conducting virtual study visits. During an interview with the US-based breast cancer oncologist before NIH’s guidelines, she said that as early as last week, a couple of clinical trial patients were concerned about coming to the hospital. While follow-ups for ongoing studies continue, Hoque’s centre is using online messages to quell patients’ anxiety.
During these unprecedented times, if a therapy under investigation does not deliver a clear benefit to a patient, then the patient could be moved on to another therapy that is more likely to offer efficacy, said Saltz. The FDA’s guidelines included scenarios like investigational drug withdrawal for patients in addition to general safety monitoring when it recommended evaluation of alternative methods such as phone, virtual visits, or alternative location for assessment, including local labs or imaging centres to make safety assessments.
A day prior (March 17) to the FDA’s guidelines, the Centers for Medicare and Medicaid Services (CMS) expanded coverage for telehealth services for Medicare beneficiaries through the outbreak. This, however, would only apply to clinical trial patients who are receiving a Medicare-covered drug during the trial, said Wallace, like those trials studying the impact of a drug on quality of life.
The lack of broad testing is also a significant challenge since it is unknown how many patients in an ongoing study may be asymptomatic but positive for Covid-19, said Wallace. Bear gave an example of an ongoing investigator-led trial patient whose husband was ill, and even though he had not been diagnosed yet and nor was the trial participant sick, physicians wore N95 masks at her surgery. Her situation will be re-evaluated and if her husband remains sick she will have to be tested for COVID-19 before starting the study treatment since that would cause her blood count to go down and thus put her at risk for the virus, he added. Without adequate testing, the population on a trial that is positive for COVID-19 cannot be separated out from the rest, said Wallace.
Philip said hospitals banning visits would impact monitoring clinical trials, which would slow down data collection, data clean-up and auditing. Since patients may not want to come in for a follow-up, trial sponsors will have to be lenient in allowing missed follow-ups and report them as deviations, Bear added and Dr Miles Sparrow, gastroenterologist, The Alfred Hospital, Melbourne, Australia, agreed.
Moreover, Covid-19 testing is not part of trial protocols, and it may get complicated from a regulatory and data integrity point of view, said Wallace. While trials are designed to consider messy data, the study size may not be enough to accommodate large numbers of sick patients due to Covid-19, he explained. This will also affect standard assumptions made to design a study, like the mortality risk in a geriatric study, he explained.
While previously a trial showing statistical significance would have been enough, the data will now be scrutinized, especially with respect to pulmonary side effects, which will be a concern moving forward, said Saltz. While there is a chance the pandemic may not be a major factor in the outcome of clinical trials, it would certainly muddy the waters with regards to efficacy data, said DePinho. The FDA also acknowledged in its guidance that there may be unavoidable protocol deviations due to Covid-19.
Manasi Vaidya and Reynald Castaneda are Senior Reporters for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.