Need to Know:
- Using the GlobalData Clinical Trials database, Clinical Trials Arena can reveal the breakdown of disrupted clinical trials in the past two years. We also extracted ClinicalTrials.gov data to examine clinical trial initiation delays and status changes in detail. We then interviewed investigators to add context to why certain therapeutic areas had contrasting levels of clinical trial activity.
- We found that trials in toxicology and neurological conditions were among the most frequently suspended, delayed, or prematurely concluded. In contrast, oncology trials – particularly for skin cancer – were most able to continue operations without major disruption.
- According to investigators, patients who previously deferred their periodic check-ups, as well as sponsors that delayed trial initiations, are now coming back to clinics – which allows for clinical trial activity to start recuperating. But there are still lingering obstacles, such as staff shortages and delays in funding and regulatory reviews, especially affecting certain disease areas.
When the Covid-19 pandemic first hit in March 2020, it led to an immediate boom in Covid-19 clinical trials. But progress in other therapeutic areas stalled: sponsors suspended enrolment, initiation dates pushed back, and many trials terminated.
In the first six months of the pandemic, trial enrolments dropped because of the risk of Covid-19 infection at clinical trial sites such as hospitals, and investigators pivoted toward Covid-19 research or were furloughed, explains Brooke Wilson, associate director, GlobalData Clinical Trials Intelligence. Some trials were too high-risk to continue, such as heart transplant trials where the patient must be immune suppressed, she adds. Many hospitals’ operating rooms became intensive care units, causing disruption to trials with elective heart or kidney surgery, she notes. GlobalData is the parent company of Clinical Trials Arena.
Some two years later, clinical trials progress appears to be on track to recover, based on data and our interviews with investigators. But this high-level view masks asymmetric impacts at a therapeutic level, with many conditions being more severely affected by the pandemic and taking longer to recover.
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To examine the impacts of the pandemic in detail, we used archived ClinicalTrials.gov data from the Clinical Trials Transformation Initiative. Using monthly archived data going back to January 2018 allowed us to identify the historic status and anticipated start date of each trial. By stitching these data snapshots into a single dataset, we were able to track when trial initiation delays occurred and when trials were reported as suspended and resumed.
Variation in restarting suspended clinical trials
Clinical Trials Arena’s analysis found that overall, 7% of trials with US sites that were in the recruiting phase during the first quarter of 2020 were at some point reported as suspended during the next two years.
Nausea and obesity trials were among the most likely to experience suspensions in early 2020, with 11% and 10% of studies suspended, respectively. Some oncology conditions such as sarcomas and gynaecological cancer also had high suspension rates. However, trials for these four disease areas had very low non-resumption rates: around nine in ten suspended trials have since resumed recruitment, often after only a couple of months of inactivity.
Inversely, non-resumption rates were far higher for many other conditions. For example, for psychiatric disorders, where one in 10 trials were reported as suspended, half of those have not resumed activity to date. For obesity and diabetes, the non-resumption rates have been 36% and 35%, respectively.
A caveat with analysing clinical registry data is that analysis relies on sponsors providing updates in a timely manner. While our findings almost certainly underestimate the true overall impact of the pandemic on the sector, they still offer unique insight into which areas have been most heavily affected.
Toxicology clinical trials severely impacted
Toxicology trials experienced both high initiation delays during the pandemic and high rates of recruiting trials being suspended. Between April and September 2020, 8% of recruiting toxicology trials reported suspensions, higher than the equivalent rates for oncology (5%) and infectious disease (6%).
Toxicology trials were also slower to resume. In the third quarter of 2020, recently resumed trials made up 2% of all active non-toxicology trials. In comparison, only 1% of toxicology trials were newly resumed.
Toxicology trials are designed to look at safe dosing regimens and for toxicity risks, GlobalData’s Wilson explains. The GlobalData Clinical Trials database shows that, in the top drugs in the toxicology category, many of these trials are for the steroid dexamethasone, which is a chemo-induced nausea treatment, she adds. In the past two years, cancer patients, many of whom are immune compromised, may have been less inclined to come into a hospital just to try anti-nausea medication, she notes.
On a positive note, clinical trials in certain indications persisted through the pandemic. Skin-level oncology trials were among the least likely to see recruitment suspended. Bacterial infections, which saw large trial initiation delays, also had relatively few suspended trials – just 4% of recruiting trials in early 2020 would be reported as suspended at any stage over the next two years.
Melanoma investigator Dr Ahmad Tarhini says while there was some slowdown in the early months of the pandemic, skin-level oncology clinical trial sites adapted quickly. The motivation to keep trials going is the urgency for treatment right after diagnosis, explained Tarhini, cutaneous clinical and translational research director at the Moffitt Cancer Center.
More than 300 clinical trials stopped
As for all clinical trials that were stopped altogether during 2020 and 2021, 339 trials had premature conclusions with disruption due to the pandemic listed as the culprit. This accounts for 2.2% of all trials that concluded during this period.
For cerebrovascular and neurocognitive disorder trials, the rate was far higher. Specifically, their respective rates of trials concluding prematurely due to Covid-19 were 5.2% and 4.5%. Premature conclusion rates were also above average for other neurological conditions including brain disease, neurodegenerative disease, and neurologic manifestations.
Cerebrovascular disease investigator Dr David Liebeskind notes that the prominence of stroke cases didn’t diminish in the past two years; it’s just that the referral pathway has changed. Cerebrovascular disorder investigator Aristeidis Katsanos adds that it was harder to approach potential patients to participate in clinical trials in the past two years as they did not want to do additional medical tests necessary for such investigations. Patients with mild stroke and transient ischemic attack deferred hospital visits, and thus made it harder to find these patients for trials, adds Katsanos, neurology assistant professor, McMaster University, Ontario, Canada.
Stroke patients with a SARS-CoV-2 infection were not unusual, notes Liebeskind, neurology professor at UCLA. And patients who have both issues are not ideal for typical stroke clinical trials as they have different treatment schedules, he explains. Having both conditions increase a patient’s risk of mortality, Katsanos adds.
That said, Katsanos notes clinical trial activity at his center is building momentum. In clinical trials he is designing now, remote visits are being actively integrated into the design, he adds. With UCLA having staff working from home, trials have adapted remote enrolment, remote consent, and remote follow-up visits, Liebeskind says. Clinical Trials Arena previously investigated the ubiquity of remote clinical trial monitoring.
Initiation delays detailed
While it may be known that the pandemic triggered broad clinical trial initiation delays, the magnitude of such delays is not yet clear. And so, to measure initiation delays, we looked at the percentage of trials that ultimately started more than six months after their anticipated start date. We defined these trials as “significantly delayed”. For this analysis, we excluded trials where the initiation date was only added to ClinicalTrials.gov after the trial had already begun, as it was not possible to identify the original planned start for these trials.
Prior to the pandemic, toxicology trials were already the most likely to experience initiation delays, with almost one in three trials being significantly delayed between January 2018 and October 2019. Once Covid-19 hit, this figure rose sharply to 58%. For many therapy areas, start delays returned to normal levels towards the end of 2020. But this was not the case with toxicology as delays remained high.
Initiation delays in traditionally punctual trials
We also saw that initiation delays increased significantly in many disease areas where trials traditionally began closer to their planned start dates. One example is in coronary disease. In 2019, fewer than 20% of these trials experienced significant initiation delays, but during the peak of the pandemic, 50% of coronary disease trials were delayed more than six months.
Cardiovascular disease and diabetes investigator Dr Matthew Budoff says for any stable disease that doesn’t mandate regular follow up, patients were particularly likely to defer their visits during lockdowns. He says he hasn’t seen some of his patients for two years, adding: “And if I can’t see them, I can’t enrol in trials.” These patients would typically have biannual or annual visits. Even patients with mild symptoms would defer visits, adds Budoff, medicine professor at UCLA.
At present, most practices are likely to be seeing an above average number of patients as they are making up for skipped visits in the past two years, Budoff says. Companies are seemingly also playing catch-up on clinical trial initiation, with certain companies that have delayed their trials in the past two years now starting or looking to start trials, he adds. Here arises a challenge: the potential for trials initiated would outnumber the patients available to participate in trials, he notes.
Substance-related disorder trials face delays
Following a summer of high disruption in 2020, initiation delays quickly recovered to near pre-pandemic levels for most indications. However, certain conditions continued to experience high delays after the peak of the pandemic passed. Solid tumour trials, for example, with a significant delay rate of just 9% prior to the pandemic, saw a doubling of trials delayed over six months in the summer of 2020. For trials due to start towards the end of 2020, the last point at which this analysis is methodologically feasible, the significant delay rate remained at 20%.
Other conditions that saw a sharp increase in trials delayed over six months during 2020 included psychiatric and mental disorders, as well as substance-related disorders and cerebrovascular disorders.
Substance-related disorders investigator Steven Shoptaw, PhD, says bureaucracy is the biggest obstacle to getting clinical trials started. “I have never seen the slowness of bureaucracy I see today. Two years of perpetual delays, meaning it’s hard to get papers off the desk.” Funding, regulatory, and IRB reviews were a lot slower in the past two years and at present, even slower than pre-pandemic, he adds. And this is frustrating, as there is a public health urgency surrounding substance abuse, particularly in Los Angeles, notes Shoptaw, director of the Center for Behavioral and Addiction Medicine at UCLA.
One of the challenges faced by substance-related disorder trials is that they are not well suited to the inclusion of certain decentralised approaches, Shoptaw adds. These clinical trials need a sense of social connection and so certain digital approaches like telehealth are not ideal, he says. Participants need to feel connected, to feel a part of the treatment and research experience, he explains. Clinical Trials Arena previously explained why telemedicine has yet to catch up on dermatology clinical trial demands.
But this does not mean decentralisation has been done away with altogether. Shoptaw is involved in running a clinical trial with a medical van directly going to drug addiction patients who also have infectious diseases like HIV. Clinical Trials Arena also previously reported on the challenges of a direct-to-patient approach, specifically on remote drug deliveries.
US trials more likely to register major delays
One final finding is that single-country trials located in the US were the most likely to register significant delays to initiation during 2020. In the previous two years, fewer than one in four single-country US trials ultimately began more than six months after their initial planned start date. During the pandemic this figure rose sharply, peaking at 43% for trials due to start during the first quarter of 2020.
Initiation delays were also significant for single-country trials in the UK, while trials spread across multiple countries and those located in China reported fewer substantial increases in delays due to the pandemic.
As we look ahead to the next stage of the pandemic, many challenges remain. Staff shortages, and delayed funding and regulatory reviews are all limiting factors in trial activity. The risk of more virulent SARS-CoV-2 variants that could still emerge are also on the minds of investigators, with their potential to shake up operations.
Nevertheless, this analysis adds further evidence that decentralised clinical trial elements will still be used as lockdown measures are eased. In fact, any clinical trial approach that ensures investigations are as nimble as possible will likely gain uptake to allow studies to rapidly adapt to a changing world. As Liebeskind puts it: “Times have changed – and as a result, clinical trials have to change.”
