April 14, 2020
As the number of coronavirus cases continue to rise across the country, the pressure is on to find a vaccine and treatment options effective against COVID-19.
Health officials say even with loosening of federal guidelines, new drug treatments must undergo rigorous evaluation to prove safety and efficacy before being approved.
The design of a clinical trial – particularly the participants and treatment or procedure being studied – influences the the timeline for producing results, clinical researchers say.
Clinical trials are most commonly used to determine whether a new drug, combination of drugs, medical device or approach to surgery is safe and effective. But before a treatment or procedure can even get to the clinical trial stage, in which people volunteer as test participants, it must first show promise in a lab setting and among animals.
All clinical trials must follow a protocol designed to balance the benefits and risks to the participants, according to the National Institutes of Health. Each trial is led by a principal investigator.
Clinical trials are conducted in phases, each one with its own purpose. Phase I trials focus on the safety of the intervention, looking to determine any potential side effects among a small number of participants. Phase II trials measure both effectiveness and safety in a larger population. Phase III trials involve even larger groups of participants to confirm effectiveness, monitor side effects, and draw comparisons to either the current standard of care or other treatment options.
Phase IV trials happen after the U.S. Food and Drug Administration grants approval and the new drug or treatment becomes available to the public. Its purpose is to continue to track safety and effectiveness.
To determine effectiveness, a new drug or treatment usually is compared to either a placebo or the standard of care. In randomized controlled trials, participants are randomized to either the new intervention or to the other group.
The urgency for a COVID-19 treatment options has led the U.S. Food and Drug Administration fast-track potential therapies through its Coronavirus Treatment Acceleration Program. The agency is cutting some of the red tape involved in the approval process in hopes of quickly identifying treatments – while still ensuring they are safe and effective.
As a part of these efforts, the FDA is providing rapid feedback to developers and scientists, in some cases reviewing study protocols within 24 hours. The agency also is working to create protocols that can streamline efforts across institutions and programs.
Ed Seguine, CEO of Clinical Ink, believes a better application of technology could speed up the clinical trial process, too. Seguine works on the operational side of clinical trials, offering researchers technology to streamline data collection.
In some trials, clinical data is recorded on paper and later typed into the computer system, he said. That can lead to weeks-long delays because researchers also must treat patients.
"We have developed a tablet-based platform that can be used when it matters at the patient visit," Seguine said. "We build forms that include all the data required for the patient visit. This way the evidence is available instantly and can be accessed across the world."
Clinical Ink was chosen to run some of the largest Ebola trials and is actively working on two COVID-19 related studies, one of which starts on April 21st.
"There is need for speed right now," he emphasized. "It still takes a while to enroll the number of patients needed and to see efficacy, but we can shorten that time by using modern technology."
There are already many COVID-19 trials ongoing or in the process of being launched. The contenders for possible treatments include nitric oxide – the gas that led to Viagra, plasma donations from COVID-19 survivors, and drugs like hydroxychloroquine and remdesivir.
Emma Meagher, Penn Medicine's chief clinical research officer, and Steven Libutti, director of the Rutgers Cancer Institute, said the timeline of a clinical trial depends on a variety of factors, including the its design, the interventions being studied and the specific clinical endpoints being measured.
Both Rutgers and Penn Medicine are conducting their own COVID-19 trials. One of Penn's trials is focusing on whether plasma taken from a recovering COVID-19 patient can help those battling severe coronavirus complications recover more quickly.
People who recover from COVID-19 develop antibodies to the disease, which build up over time, Meagher said. During a process called plasmapheresis, plasma containing antibodies is separated from donated blood cells and transfused into a sick patient. The hope is that the antibodies will help the patient fight off the infection.
Two separate protocols – a donor registry, which is already underway, and a clinical trial involving two sub-studies – have been designed, Meagher said. One of the sub-studies will investigate outcomes of the treatment in patients hospitalized with severe disease, but who are not in the intensive care unit. The other will focus on patients in the ICU.
The researchers are submitting an Investigational New Drug application to the FDA this week and will start enrolling patients into the clinical trial once they receive approval. Overall, the trial will involve 50 patients and will take four weeks to four months to complete, depending on the availability of eligible patients.
"Appreciating the urgency to come up with treatments for COVID-19, it is remarkable that the principal investigators pulled together the donor registry and clinical trial in such a short time," Meagher said. "It is really impressive what they have done."
The Rutgers Cancer Institute of New Jersey trial is exploring the benefits of treating COVID-19 patients with hydroxychloroquine alone and in combination with azithromycin.
Enrolling patients shouldn't be too difficult – as long as inclusion and exclusion criteria aren't too difficult, should be relatively easy because COVID-19 is unfortunately now common in the general population, Libutti said. Neither should it be too challenging to complete a trial – depending on how long patients need to be followed to determine results.
Rutgers researchers will be measuring the amount of the virus in the blood to see which treatment causes the viral load to go down most significantly. They should have 160 patients enrolled by the end of April and results by mid-May, although they will continue to follow the patients for 6 months, Libutti said.
"Any treatment is a balance of benefit and side effect, and there is always an element of chance," Libutti said. "You have to predict how much a difference there will be between the two groups being compared. The bigger the difference predicted, the less patients needed in the study. The smaller difference predicted, the more needed."
The two groups being compared need to look as similar as possible when it comes to demographics, level of disease and comorbidities, he said. That way, the only differing factor is the drug being tested.
Determining the number of patients necessary and finding willing participants who meet all inclusion and exclusion criteria also can affect a trial's timeline, Meagher added. So can the tolerability of the drug being studied. If participants need to drop out of the study due to side effects, extra time is needed to replace them.
"You need to assess each trial on its own merits and on how feasible it is to get it done," she said.