Valuable Thoughts on Trial Enrollment, Critical of Current Unfolding Dynamics

Valuable Thoughts on Trial Enrollment, Takes Swipe at Less Rigorous Practices

In a July 15 opinion piece, “Improving Clinical Trial Enrollment — In the Covid-19 Era and Beyond,” The New England Journal of Medicine offers some key insights for our industry. They note that of the over 3 million COVID-19 cases in the US, active clinical trials could only enroll about 4% of these folks. Perhaps unrealistically, they say that, “In the face of a new disease in dire need of proven treatments, every patient not offered enrollment in a well-designed, well-conducted study represents a missed opportunity to advance scientific knowledge, develop therapeutic strategies, and ultimately improve care for everyone who will come next.” Noting the necessity of a broad international trial infrastructure, NEJM says, “Without it, clinical gestalt and idiosyncratic practice variation become the foundation for so-called standards of care.” In taking this view, they are challenging the validity of work such as the West Texas doctor or the Peruvian universities and doctors we have profiled at TrialSite News. 

Noting widespread off-label, off-trial use of medicines from HCQ to statins, etc., they argue that “demonstrated benefit” must be shown beyond mere plausibility of a treatment. This means that instead of “enrolling the smallest number of participants required to power definitive trials, such practice patterns expose thousands of patients to the potential risks of untested interventions with no reliable way of drawing conclusions about efficacy and safety.” Outlining some of the difficulties facing actual clinical trials, it is noted that there is competition between the resources needed for clinical trial work and those needed for direct health care. While usually taking a year or more to launch, they note that, “In this pandemic, the critical volume of patients compressed that time frame, in some cases to a matter of weeks. With hundreds of proposed interventions, medical centers faced choices about how to prioritize potential trials.”

Massachusetts General Gets to Work

The authors’ hospital, Massachusetts General Hospital, “established a centralized scientific review committee, in addition to the ethical oversight of the institutional review board, to determine the portfolio of Covid-19–related trials that would be launched and to continuously evaluate newly proposed studies.”

The committee focused on asking: how important and answerable is the research question; are there multiple sites for the trial to build-in redundancy; and what “logistical considerations” come into play. This “process ensures that selected trials are diverse in approach, targeted at multiple viral and host pathways, and structured to maximize the chance that the research question will be definitively answered.”

Next, centralizing “key elements shared among trials” is important, e.g. to prevent, “prioritization of the best-funded trial over those with the greatest potential impact.” Also, “rather than requiring each study team to provide personnel to draw blood for laboratory tests, administer study drugs, and organize data entry, a core group coordinated these procedures across trials.” 

As an example, “Having eight or more trials seeking to enroll patients on a given day crystallizes the logistic challenges of simultaneously conducting studies that broadly target the same patient population.” Without coordination, study teams “each create their own independent processes for identifying and approaching patients.” This advantages large teams and can be confusing for patient and their families. 

How to Find Patients

Looking at more models of how to find subjects, using “inpatient care teams” as the referring source could, “lead to referrals based on arbitrary factors such as which trial a particular clinician happened to have heard about — and it would risk missing eligible participants altogether.” Another idea would be a rotating schedule that would prioritize each trial on a certain day of the week, “but given the variation in daily admissions (Sunday mornings, we noticed, often had the fewest new admissions), this approach could introduce unpredictable, systematic bias into the selection process.” So instead, the hospital, “developed a process for centrally identifying and screening, according to each trial’s inclusion and exclusion criteria, every patient newly admitted to the hospital or newly diagnosed with Covid-19, and for organizing the way they would be approached for enrollment.” The process is similar to those used at other hospital systems. 

Mass General Using Unified Recruitment Processes; Questions Remain

Questions remaining include, “what is the right amount of information to provide to study participants that enhances rather than obfuscates informed consent?” Does the COVID-19-forced separation from family members impact informed consent? How is the media affecting, “patients’ interest in clinical trials?” The Massachusetts General protocol has so far screened over 1300 patients for 11 trials. Since the pandemic began, over 350 persons have been enrolled. Also, “A rapidly evolving trial landscape has to build on new data as they emerge. For example, after it was announced that the remdesivir trial had met its primary end point, all currently enrolling studies either had to allow patients to receive remdesivir or could approach patients only after they were evaluated for remdesivir as part of standard care under the emergency use authorization.”

Three Future Directions

Per TNEJM, three “future directions” are key: 1) maximizing trial access and enrollment to find the best COVID-19 care; 2) “we must improve national platforms to promote collaboration in clinical trials. A trial infrastructure fixed in a single location is inadequate for targeting a virus that is moving through geographic hot spots;” and 3) “we should adapt this research infrastructure to answer questions beyond Covid-19.” In closing, the authors note that, “Every day in clinical practice, we apply so-called standards of care that are based not on good data but on expert opinion that is ripe for a challenge in the form of a randomized trial.” 

We at TrialSite News appreciate NEJM’s efforts to improve the recruitment process in this time of pandemic. At the same time, we wonder if they might present a false dichotomy between “hard science” and old-fashioned clinicians’ knowledge, training, instincts, and “on the ground” results. Obviously, we want to apply the best science we can in fighting disease. But in the real world, for example the Peruvian work we have covered, the resources for “best practices” may not exist. Perhaps the issue can be framed this way: is there a place for “guerrilla warfare” alongside the formal, declared international war against COVID-19?