COVID-19 is disrupting society and healthcare in numerous profound ways. One way that is currently being overlooked, though, is the disruption to ongoing or planned clinical trials. While these disruptions appear inevitable in the short term, there are ways to mitigate the effects of these disturbances on the long-term goal of seeking approval for a new drug or indication.
While some have viewed clinical trials as merely a bureaucratic burden for pharmaceutical companies, or simply a way for pharmaceutical companies to make more money off of slightly different indications, clinical trials are in fact much more significant and important. They are the fundamental means by which we gain knowledge about the therapeutic benefit of potential new medicines or indications for existing medicines, and are required in order for the U.S. Food and Drug Administration (FDA or the Agency) to approve these advancements.
It is heartening to see how many clinical trial enrollees are dedicated to not only seeking a cure or clinical benefit for themselves, but also to contributing to the common goal of scientific understanding—even in the face of potential risk to their own health. Clinical trial participants often must sacrifice their time and undergo uncomfortable therapies or procedures all in an effort to eke out knowledge from the unknown. These volunteers participate in the process for a myriad of reasons, including personal and altruistic. Sponsors that are conducting these trials must be good stewards of the data and results that are gathered from these trials. As Buckminster Fuller noted, there is no such thing as negative knowledge.
However, COVID-19 is disrupting the ability to continue to conduct these trials as planned for a number of reasons: (1) they cannot enroll participants, (2) subjects cannot visit large healthcare facilities, (3) subjects cannot obtain the treatment and monitoring from their healthcare professionals involved in the trial, (4) subjects may drop out due to issues caused by COVID-19, or (5) subjects cannot have their data accurately recorded due to the disruptions. Additionally, some trials that depend upon measurements of patients’ well-being are being influenced by the anxiety and stress that COVID-19 is having on society.
Many ongoing clinical trials are for serious and life-threatening conditions. It is essential that we consider steps to maintain the integrity of the data gathered to protect the sacrifices of the test subjects and to protect the public from incorrect (or no) answers produced from truncated clinical trials. Therefore, we must take all steps to continue the trials and save this clinical data that has already been gathered.
The FDA has recognized the disruption that COVID-19 has already had and will continue to have on clinical trials. In response, the FDA issued its own guidance on March 18, 2020, titled “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19” (COVID-19 Guidance Document). This guidance provides the FDA’s thoughts on how best to prepare and mitigate for the effects of COVID-19 on clinical trials. In accordance with this guidance, we offer our suggestions for how best to deal with these issues as well.
- Do nothing rashly. Make sure to gather information and review the FDA’s COVID-19 guidance document before taking action. While these are hectic times, it is important to understand the situation’s complexity before taking action. You should generally stay the course – do not stop or truncate your trial. As the legendary UCLA basketball coach, John Wooden, stated in the Pyramid of Success: Be quick – but don’t hurry.
- Review the clinical protocols and statistical action plans for your trial because they may already provide the flexibility you need. Many clinical trial protocols allow for some flexibility in analyzing collected data. Issues routinely arise in the conduct of clinical trials that create problems: clinical trial supplies are fumbled, patients are unable to make appointments for treatment or monitoring, some investigators are sloppy in their observations, data is lost or misreported or site enrollments are skewed. The list goes on. That is why procedures have evolved to deal with these issues, and they can often be adapted to today’s circumstances.
- Consider new data collection options. Telemedicine options are obvious. Other options include using satellite clinics and contracting with visiting healthcare professionals, including emergency medical technicians. Contract healthcare ride services exist to get patients to satellite observation sites. All of these options require discussions with the site principal investigator, the person in charge of the trial site, and their staff to see what capabilities they have and are willing to accept. The FDA recognizes the value of all clinical data, therefore, you may find an ally in the Agency when you are trying to think of solutions to rescue your data. This point is particularly critical since as many as half the drugs under development are orphan drugs that are needed for serious orphan diseases.
- Consider new statistical methods to analyze the data already acquired. We already know of one clinical trial that was forced to end early but was able to take steps to mitigate the effect. Those involved with running the clinical trial were able to find that the use of an alternative statistical model would likely provide sufficient evidence to show that the therapeutic intervention was effective. Thus, much of the data from the trial was salvaged.
- Think about how the new disruptions will affect research subjects’ lives, and take efforts to mitigate those issues. For example, how do you ensure that a contract healthcare provider who goes to a subject does not increase that subject’s risk of contracting COVID-19? If the subject cannot come to the hospital, could a mobile app be created and sent that is workable for a subject? All of these issues are manageable, but they need to be thoroughly assessed. The key is protecting the data that has been collected thus far. Make sure to keep the subjects and investigators involved and engaged to the extent possible.
- When the crisis passes, you want to have access to any data collected in the hiatus. Those data have to be as good as possible, and then you can decide if you want to continue as initially planned. Even if you continue, you should assess how the alternative methods could work, and maintain the alternatives during the trial. You may even want to re-randomize between the two trial arms, which may increase the value of information gathered in the interim or hiatus.
- Consider new data capture plans and/or procedures. Flexibility often exists in data capture until the final statistical analysis plan is finalized. New statistical tests are constantly being developed, especially to deal with missing data. Historically, “last observation carried forward” has been used but has been considered less than ideal. New superior models and algorithms have been developed to address these issues – for example, simulations based on re-randomizations of existing data. The most important thing to know is that options exist regarding different statistical methods. Make sure to have discussions with your statisticians to consider all potential issues.
- Review the Investigators Brochure, Informed Consent Forms, and Clinical Report Forms. Ultimately, you will need to contact your clinical investigators and clinical trial subjects to discuss any forthcoming changes. Accordingly, you will also need to discuss these issues with your Institutional Review Board (IRB) and Data Monitoring Board (DMB). You want to be prepared for those discussions because time will be critical. Hopefully you have maintained a dialogue with the IRB and the DMB. Discuss options with them.
- Talk to the FDA. The Agency is often seen as an opponent, but they too want to make sure that clinical trial data does not go to waste. Remember that, while you have seen your own clinical trial, the FDA has also seen all of them. The FDA knows how to handle changes to clinical trials and knows what to expect in many cases. Reach out to them for their input.
- Lastly, prepare a plan and a script for implementing the final plan. Hopefully, these new plans will help ensure that your trial data is utilized and that your clinical trial will still be a success.
Remaining nimble in these changing times is critical, including in the world of clinical trials. Staying focused and pragmatic—and seeking the FDA’s advice when warranted—will help smooth the inevitable bumps in the road caused by COVID-19.
Outside Contributor: Dr. Brent A. Blumenstein of Triac Consulting