Sanjeev Luther

We are all familiar with the disruption that the COVID-19 pandemic has caused to healthcare delivery. But what may be less familiar is its effect on clinical trials. Science depends on clinical trials to illuminate best practices, set standards of care and test new therapies. Thousands of clinical trials have been suspended or halted

 since the onset of the pandemic, dramatically slowing the pace of scientific progress.

Despite the pandemic, however, our company, Rafael Pharmaceuticals, successfully enrolled 500 participants in its multicenter AVENGER 500 trial

 for metastatic pancreatic cancer. The trial, the only Phase III trial of a novel agent for metastatic pancreatic cancer, compares the safety and efficacy of a combination of Rafael’s lead compound CPI-613

 (devimistat) and modified FOLFIRINOX, a chemotherapy cocktail, with standard FOLFIRINOX alone. 

Though conducting a large clinical trial (75 sites in 12 countries) during a pandemic posed enormous challenges, it also catalyzed the identification and adoption of innovative approaches that will shape future clinical trials long after the pandemic has passed.

The limited options for metastatic pancreatic cancer

Pancreatic cancer is the most aggressive common cancer, with a five-year survival rate for metastatic disease of only 1 percent.

 Although the incidence in the United States is still relatively low (about 60,000 are expected to be diagnosed in 2021), it has grown to the point that it is now the second leading cause of cancer death.

 Because it is usually detected only at a late stage, the window of opportunity for identifying and treating trial participants is narrow. 

The severity of the disease, however, is also a strong motivator for enrollment. Though we were pressured by some of our sites to halt the trial because of the pandemic, this was never an option. On the contrary, our goal was to enroll participants as quickly as possible so that they could benefit from the life-saving potential of devimistat. We also wanted to avoid the complications of having to restart the trial at a future time. 

As a result, we completed enrollment 17 months ahead of schedule, in August of 2020.

 Though this was a good thing, it led to a disconnect between enrollment and data availability that we are still dealing with: though we enrolled participants at a blistering pace, data processing lagged behind. One lesson for future trials would be to strive to find the right balance between enrollment and data monitoring.

Another cancer-related pandemic challenge was the health of the trial participants. Although recruiting during the pandemic wasn’t the issue for us that it has been in other trials because of the lack of treatment options for metastatic pancreatic cancer, conducting a trial with participants who were not only extremely ill, but also in many cases elderly, fragile and immunocompromised, presented its own set of complications.

To address this, we formed an internal COVID-19 task force of employees with relevant clinical, medical and pharmacovigilance expertise. Although the task force was formed to address the impact of the pandemic, we found it to be an extraordinarily useful tool that allowed us to quickly respond to the rapidly shifting on-the-ground situation, and one that could serve as a blueprint for future trial-related crises or public health emergencies.

The chief priority of the COVID-19 task force was patient safety. As one might expect, navigating changing pandemic conditions at 75 sites in 12 countries, as well as varying state, federal and institutional regulations was a huge challenge.

Unlike trials that were able to move functions to smaller facilities or even to home or virtual settings, our only option was in-person clinical visits because the treatment needed to be prepared and infused at a hospital, usually a large medical center. Though we couldn’t control the risk of contagion associated with these in-person visits, we could moderate it by keeping close track of local COVID-19 conditions.

To accomplish this, the task force met daily at 7 a.m. to make recommendations based on a review of conditions at our sites. For this, we relied heavily on data from the Johns Hopkins Coronavirus Resource Center. If the virus was spiking in New York City, for example, we would halt enrollment there and ramp up enrollment in Kansas City; if the incidence was high in Belgium, we would shift our focus to France.

Fortunately, because of their special requirements, oncology infusion centers are typically located in secure facilities that are removed from the general hospital patient population, which also helped mitigate the risk of contagion. 

We were also able to reduce risk through minor modifications to trial guidelines, for instance by reducing the frequency of in-person health status monitoring visits or allowing follow-up tests to be conducted by providers near participants’ homes. The U.S. Food and Drug Administration (FDA) was enormously helpful in working with us to modify guidelines and processes to accommodate patient safety without compromising the rigor of the research protocol. 

Indeed, adaptability was the watchword when dealing with the pandemic. One challenge was COVID-19-related restrictions placed on hospital access, which prohibited representatives of the contract research organizations (CROs) that manage our trials from accessing our sites to audit and verify data.

 caused by the pandemic also demanded that we be adaptable. Nurses and other hospital staff were diverted to the care of COVID-19 patients, became sick themselves, chose to work from home or were furloughed or laid off due to pandemic-related financial pressures on hospitals caused by reduced patient volumes, canceled elective procedures and increased expenses.

As with the FDA, the collaborative relationships with our CROs have been critical. Although we have always worked closely with them, they became even more of an extension of our company during the pandemic. That said, the pandemic also highlighted the need of a small company like ours to build our internal core competency in trial management, which we have accomplished by hiring new employees with trial-related expertise.

Thinking more critically about trial design

The pandemic has also exposed areas in which trial design can be improved. One such area is the “open label” control arm design, in which the controls know they are not receiving the test therapy. The open label control arm design reduced the motivation of controls to continue in the midst of the pandemic. If they weren’t going to receive the test therapy, their thinking went, they might as well continue with the standard treatment at a local hospital.

Though this problem was exacerbated by the pandemic, the issue of patient retention among open label control arm participants remains a design flaw in trials involving severely ill patients who can potentially benefit from the test therapy. In the future, we would advocate flexible trial designs with smaller control arms—for instance, with a two-to-one allocation ratio of test arm to control arm participants, instead of the typical one-to-one ratio.

Another adjustment in trial design would be to simplify by limiting the number of endpoints. The AVENGER 500 trial had multiple endpoints, which complicated the design at a time that was already rife with complications due to the pandemic.

Lastly, I want to touch on the importance of passion. This trial is perhaps unique in the passion it has inspired among employees, nearly all of whom have a friend or family member who has died of cancer. Because devimistat is a drug that targets metabolic processes unique to cancer, it offers promise not only for pancreatic cancer patients, but also for the millions suffering from hard-to-treat cancers with limited treatment options. 

Without this treatment, these patients would likely have died, which was the strongest motivator for dealing with the plethora of inconveniences, challenges and roadblocks caused by the pandemic. As we have often said, cancer won’t wait for COVID-19 to end.

is the President and Chief Executive Officer of 

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31787-6/fulltext

https://www.globenewswire.com/news-release/2020/08/06/2074264/0/en/Rafael-Pharmaceuticals-Achieves-Target-Enrollment-of-500-Patients-in-Pivotal-Phase-3-Trial-AVENGER-500-of-CPI-613-%EF%B8%8F-devimistat-for-Patients-with-Metastatic-Pancreatic-Cancer.html

https://rafaelpharma.com/wp-content/uploads/Rafael-Website-CPI-613-Fact-Sheet-2.pdf

https://www.cancer.org/cancer/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html

https://pubmed.ncbi.nlm.nih.gov/24840647/

https://www.beckershospitalreview.com/finance/49-hospitals-furloughing-workers-in-response-to-covid-19.html

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