Covid-19 Impacts on Clinical Trials

By: Sarah Johnson

As many of us begin our sixth week in quarantine, the repercussions of Covid-19 are becoming more and more apparent. One important issue is the influence Covid-19 is having on (non Covid-19 related) clinical trials. So this week I’m taking a closer look at what clinical trials are and how they are being impacted by the pandemic.

What are clinical trials?

According to the US Department of Health and Human Services, clinical trials are research studies performed on people that evaluate a medical, surgical, or behavioral intervention. They are the primary method researchers use to assess if a new treatment (usually a new drug, diet, or medical device) is safe and effective for people and the situation they are attempting to improve. Sometimes, trials are used to try to treat something in a completely new way, but most of the time, trials are used to test if a new treatment is more effective and/or has less harmful side effects than whatever has been accepted as “the standard” treatment. There are four phases that make up a clinical trial.

• During Phase I of a trial, professionals preform tests of the experimental treatment on a small group of, often healthy, people to judge its safety, find side effects, and establish the correct drug dosage. Phase I’s emphasis is safety.
• During Phase II of a trial, the trial is opened up to more people (100 to 300). The emphasis in Phase II is effectiveness and this phase can last several years. Along with continuing to study safety, with an emphasis on short-term side effects, this phase attempts to obtain preliminary data on whether the treatment works in people who have a certain condition.
• During Phase III of a trial, the professionals administering the trial gather more information about safety and effectiveness of the treatment. This means looking into the treatment’s effectiveness within different populations, dosages, and with a combination of other drugs. The largest group of people participate in this phase, ranging from several hundred to about 3,000 people. If the FDA agrees that the trial results are positive, it will approve the experimental treatment, allowing it to be accessible by the public.
• Phase IV of a trial for drugs or devices takes place after the FDA approves its use. Their effectiveness and safety are monitored while it is implemented within large, diverse populations. Sometimes, the side effects of a drug may not become clear until more people have taken it for a longer period of time. If this happens, actions must be taken to either modify or discontinue the treatment to protect the public.

How is Covid-19 impacting ongoing clinical trials?

According to ICONIC, the integrity of more than 330,000 clinical trials listed on ClinicalTrials.gov are impacted by Covid-19 and as of March 26, at least 18 biotech or pharma companies have reported a disruption to a clinical trial as a result of this pandemic. Eli Lilly was the first large pharmaceutical company to announce delays to its clinical trials saying “company will delay most new study starts and pause enrollment in most ongoing studies.” Tim Garnett, M.B.B.S., Lilly’s chief medical officer, had this to say

“Lilly is working hard to alleviate some of the pressure that the global Covid-19 pandemic has placed on our healthcare system. We have repurposed our laboratories to conduct diagnostic testing for patients and we are researching potential therapeutics. In the interest of helping to ensure patient safety and minimizing further stress on the system, Lilly has also decided to take several proactive steps in regard to our clinical trial activities around the world during the Covid-19 pandemic. By delaying most new study starts and pausing enrollment of new patients or healthy volunteers in most ongoing studies, we hope to ease the burden on participating healthcare facilities and allow physicians to focus more of their efforts on combating Covid-19.”

Here are two figures demonstrating what clinical trials have been disrupted by the coronavirus pandemic by biopharmadive.

Why is COVID-19 impacting clinical trials?

COVID-19 and the associated lockdowns are extensively impacting every aspect of clinical trials — not only availability, recruitment, and administration of the trials, but immediate patient care, too. Covid-19 will also likely impact data collection and analysis in the coming months of trials that were previously underway. These delays could be detrimental to understanding the impact these treatments could have for the general public. When looking at administering trials, the FDA and trial administrators need not only keep in mind the safety and wellbeing of those involved throughout the course of the four phases, but also the integrity of the data collected throughout.
The first way Covid-19 can impact trials is that patients, administrators, and trial personal could come in contact with the virus, or contract the virus themselves. With the increased pressure to rely on contact tracing as a method to allow us to return to somewhat normal life, the probability of people involved in the study having to self quarantine due to exposure is increasing. If a participant becomes infected, they may have to leave the trial, thus giving up their hope of receiving the treatment, and, unfortunately potentially having taken the spot of someone else. Another consideration is people who enroll for and start a trial could be infected but asymptomatic, which could endanger everyone involved.

According to Science 37‘s chief medical officer,  Jonathan Cotliar,

“We are seeing a significant and growing number of cases where clinical trial participants are refusing to visit hospitals or local clinics for fear that they could be exposed to Covid-19. By all accounts, we expect this issue to continue to compound over time, which makes risk-mitigation strategies an imperative to protect the safety and well-being of participants and to enable business continuity.”

The second way the pandemic is impacting trials is that the locations (often medical facilities) needed to conduct trial activities may be repurposed or not available for use. One of the largest ideas behind the stay at home orders most of the world is currently obeying is to flatten the curve. For more information about this and Covid-19 legislation, read this blog. But, essentially, we are all staying home in hopes mitigating the spike of people falling ill to keep hospitals from becoming overrun by people who need lifesaving care all at the same time. If additional space is needed, Covid-19 patients in acute distress will take precedence over trial patients, thus putting the space available to administer these trials at risk. Even where the space is available, depending on the health of people participating in the study, participants could be hesitant, or it could be outright irresponsible for them, to visit the hospital with their condition in whatever compromised state the treatment may put them in. Also, hospitals banning visits impacts monitoring needed for clinical trials, thus governing the rate of which data is collected, cleaned, and audited.

Third, it can be very difficult to obtain the resources needed to execute a successful trial. Some patients in trials require intensive medical assessment due to the nature of the experimental treatment; the personnel, space, and equipment required for these assessments could be suddenly unavailable depending on the intensity of the outbreak in the trial’s location. Even just the basic items needed, like swabs and face masks, could be incredibly difficult to obtain. Other items may have their the supply chain impacted or completely cut off due to the limited workforce or changing priorities. If the drug needed to complete a trial becomes difficult to obtain, it could make whatever resources that were invested into the trial unusable, and potentially take away people’s abilities to participate in the trial once things get closer to “normal”.

Finally, testing for Covid-19 is not part of current trial protocols; implementing this may influence the integrity of the data needed to move trials out of the current phases they are in. According to Joel Wallace, IP partner, Schiff Hardin, Chicago, usually trials are designed to consider messy data, but the study size may not be enough to accommodate large numbers of sick patients due to Covid-19. According to Wallace, accommodating for this may also affect standard assumptions made to design a study, like the mortality risk.

What is being done? The legislation

The FDA attempted to outline some guidance for industry, investigators, and institutional review boards the help cope with these new issues requiring altered protocols for trials. The modifications needed for each study are contingent upon participant population, location, and necessary medical products.

The CARES (Coronavirus Aid, Relief, and Economic Security) Act doesn’t do much to address pre-existing clinical trials, understandably enough as there is a very long list of other pressing issues to tackle too. It does state in Part III, Mitigating Emergency Drug Shortages, that “The sponsor of a new animal drug may request the Secretary to designate a new animal drug … as a priority zoonotic animal drug.” The section further states the actions to expedite the development and review of an application requires someone “take steps to ensure that the design of clinical trials is as efficient as practicable, when scientifically appropriate, such as by utilizing novel trial designs or drug development tools (including biomarkers) that may reduce the number of animals needed for studies.”

Currently, there are 333 bills that pertain to clinical trials in general. For example this are Wisconsin bill which would have allowed for the reimbursement of certain expenses for patients participating in cancer clinical trials, a Minnesota bill that outlines treatment from approved clinical trials that is exempted from coverage, and a bill in Massachusetts that aims to ensure prescription drug cost transparency and affordability (which will be very important if the drug pipeline is cutoff and people can no longer obtain what they need). But other than the section in the CARES Act mentioned above, no state bills directly tackle clinical trial issues related to Covid-19. Yet, at least.

Covid-19 clinical trials

Although most pre-existing clinical trials are experiencing major difficulties,there has been significant progress on clinical trials that aim to find better treatments for Covid-19.  The number of trials studying Covid-19 has seen a steady growth since January, according to Clinical Trials Arena,  There have been mixed results from recently completed clinical trials.

On April 20th, Novartis, a Switzerland-based pharmaceutical firm, confirmed it will be conducting a clinical trial on US patients with Covid-19, examining the efficacy of antimalarial drug, hydroxychloroquine. This drug is used to prevent and treat acute attacks of malaria while also treating discoid or systemic lupus erythematosus and rheumatoid arthritis for some people. Hydroxychloroquine is a drug we have been hearing about a lot in the news, after Trump said the drug shows “tremendous promise” of working against Coronavirus at a White House briefing. Hydroxychloroquine was not developed to combat viruses, though, and has serious side effects.

There are some promising trials of an antiviral medication originally designed to target Ebola; Remdesivir. Trials started in February on patients from the Diamond Princess and two phase three trials are currently underway in the UK. Remdesivir is a nucleotide analog which interferes with the virus’s ability to replicate and was studied for SARS and MERS too. (Note: both of these drugs are not vaccines but rather ways to help very sick people fight off the virus.)

Check out this Covid-19 TrialsTracker if you are interested in keeping up with the hundreds of Covid-19 specific trials.

 

 

This is an incredibly sad episode in human existence. Tens of thousands of people have died from Covid-19 already. But, though tragic, the vast wreckage being caused by the pandemic only starts with the immediate, direct loss of life. The scope of the impact Covid-19 will have on delays, suspension, and irregularities for clinical trials, like almost everything influenced by this swelling pandemic, is hard to quantify – only time will tell.

Cover Photo by CDC on Unsplash

 

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